Joseph Cheung, MD, MS

All Publications

• Automatic, ECG-based detection of autonomic arousals and their association with cortical arousals, leg movements, and respiratory events in sleep. Sleep Olsen, M., Schneider, L. D., Cheung, J., Peppard, P. E., Jennum, P. J., Mignot, E., Sorensen, H. B. 2018

  Abstract

  The current definition of sleep arousals neglects to address the diversity of arousals and their systemic cohesion. Autonomic arousals (AA) are autonomic activations often associated with cortical arousals (CA), but they may also occur in isolation in relation to a respiratory event, a leg movement event or spontaneously, without any other physiological associations. AA should be acknowledged as essential events to understand and explore the systemic implications of arousals.We developed an automatic AA detection algorithm based on intelligent feature selection and advanced machine learning using the electrocardiogram. The model was trained and tested with respect to CA systematically scored in 258 (181 training size/77 test size) polysomnographic recordings from the Wisconsin Sleep Cohort.A precision value of 0.72 and a sensitivity of 0.63 were achieved when evaluated with respect to CA. Further analysis indicated that 81% of the non-CA-associated AAs were associated with leg movement (38%) or respiratory (43%) events.The presented algorithm shows good performance when considering that more than 80% of the false positives (FP) found by the detection algorithm appeared in relation to either leg movement or respiratory events. This indicates that most FP constitute autonomic activations that are indistinguishable from those with cortical cohesion. The proposed algorithm provides an automatic system trained in a clinical environment, which can be utilized to analyse the systemic and clinical impacts of arousals.

  View details for DOI 10.1093/sleep/zsy006

  View details for PubMedID 29329416

• Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Smith, M. T., McCrae, C. S., Cheung, J., Martin, J. L., Harrod, C. G., Heald, J. L., Carden, K. A. 2018

  Abstract

  The purpose of this systematic review is to provide supporting evidence for a clinical practice guideline on the use of actigraphy.The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of actigraphy, sleep logs, and/or polysomnography. Statistical analyses were performed to determine the clinical significance of using actigraphy as an objective measure of sleep and circadian parameters. Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations.The literature search resulted in 81 studies that met inclusion criteria; all 81 studies provided data suitable for statistical analyses. These data demonstrate that actigraphy provides consistent objective data that is often unique from patient-reported sleep logs for some sleep parameters in adult and pediatric patients with suspected or diagnosed insomnia, circadian rhythm sleep-wake disorders, sleep-disordered breathing, central disorders of hypersomnolence, and adults with insufficient sleep syndrome. These data also demonstrate that actigraphy is not a reliable measure of periodic limb movements in adult and pediatric patients. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations.

  View details for PubMedID 29991438

• Promises and Challenges in the Use of Consumer-grade Devices for Sleep Monitoring. IEEE reviews in biomedical engineering Roomkham, S., Lovell, D., Cheung, J., Perrin, D. 2018

  Abstract

  The market for smartphones, smartwatches and wearable devices is booming. In recent years, individuals and researchers have used these devices as additional tools to monitor and track sleep, physical activity and behaviour. Their use in sleep research and clinical applications could address the difficulties scaling up studies that rely on the gold-standard, polysomnography. However, the use of commercial devices for large-scale sleep studies is not without challenges. With this in mind, this paper presents an extensive review of sleep monitoring systems and the techniques used in their development. We also discuss their performance in terms of reliability and validity. We also consider the needs and expectations of users, whether these are experts, patients, or the general public. Through this review we identify a number of challenges with current studies: a lack of standard evaluation methods for consumer-grade devices (e.g., reliability and validity assessment); limitations in the populations studied; consumer expectations of monitoring devices; constraints on the resources of consumer-grade devices (e.g., power consumption).

  View details for DOI 10.1109/RBME.2018.2811735

  View details for PubMedID 29993607

• Increased EEG Theta Spectral Power in Sleep in Myotonic Dystrophy Type 1. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Cheung, J., Ruoff, C., Moore, H., Hagerman, K. A., Perez, J., Sakamuri, S., Warby, S. C., Mignot, E., Day, J., Sampson, J. 2018; 14 (2): 229–35

  Abstract

  Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that involves the central nervous system (CNS). Individuals with DM1 commonly present with sleep dysregulation, including excessive daytime sleepiness and sleep-disordered breathing. We aim to characterize electroencephalogram (EEG) power spectra from nocturnal polysomnography (PSG) in patients with DM1 compared to matched controls to better understand the potential CNS sleep dysfunction in DM1.A retrospective, case-control (1:2) chart review of patients with DM1 (n = 18) and matched controls (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, sex, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics for the two groups were compared. Power spectral analysis of the EEG C3-M2 signal was performed using the fast Fourier transformation.Patients with DM1 had significantly increased theta percent power in stage N2 sleep compared to matched controls. Theta/beta and theta/alpha percent power spectral ratios were found to be significantly increased in stage N2, N3, all sleep stages combined, and all wake periods combined in patients with DM1 compared to controls. A significantly lower nadir O2saturation was also found in patients with DM1 versus controls.Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal PSG may reflect DM1 pathology in the CNS.

  View details for DOI 10.5664/jcsm.6940

  View details for PubMedID 29394960

  View details for PubMedCentralID PMC5786842

• The MSLT is Repeatable in Narcolepsy Type 1 But Not Narcolepsy Type 2: A Retrospective Patient Study. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Ruoff, C., Pizza, F., Trotti, L. M., Sonka, K., Vandi, S., Cheung, J., Pinto, S., Einen, M., Simakajornboon, N., Han, F., Peppard, P., Nevsimalova, S., Plazzi, G., Rye, D., Mignot, E. 2018; 14 (1): 65–74

  Abstract

  To examine repeatability of Multiple Sleep Latency Test (MSLT) results in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) according to the criteria of the International Classification of Sleep Disorders, Third Edition (ICSD-3).Repeatability of the MSLT was retrospectively evaluated in NT1 (n = 60) and NT2 (n = 54) cases, and controls (n = 15). All subjects had documented HLA-DQB1*06:02 status and/or hypocretin-1 levels from cerebrospinal fluid. All subjects had undergone 2 MSLTs (≥ 1 meeting ICSD-3 criteria for narcolepsy). Repeatability was explored in children versus adults and in those on versus not on medication(s). Subsample and multivariate analysis were performed.Both MSLTs in unmedicated patients were positive for narcolepsy in 78%, 18%, and 7% of NT1, NT2, and controls, respectively. NT2 cases changed to idiopathic hypersomnia or to a negative MSLT 26% and 57% of the time, respectively. Although NT1 cases were 10 to 14 times more likely to demonstrate a second positive MSLT compared to NT2 cases (P < 10-5) and controls (P < 10-4), respectively, NT2 cases were not significantly different from controls (P = .64). Medication use (P = .009) but not adult versus children status (P = .85) significantly decreased the likelihood of a repeat positive MSLT.In a clinical setting, a positive MSLT for narcolepsy is a more reproducible and stable feature in NT1 than NT2. The retrospective design of this study hinders interpretation of these data, as there are many different, and possibly opposing, reasons to repeat a MSLT in NT1 versus NT2 (ie, ascertainment bias). Additional systematic MSLT repeatability studies independent of confounds are ideally needed to confirm these findings.

  View details for DOI 10.5664/jcsm.6882

  View details for PubMedID 29198301

  View details for PubMedCentralID PMC5734895

• Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Smith, M. T., McCrae, C. S., Cheung, J., Martin, J. L., Harrod, C. G., Heald, J. L., Carden, K. A. 2018

  Abstract

  The purpose of this guideline is to establish clinical practice recommendations for the use of actigraphy in adult and pediatric patients with suspected or diagnosed sleep disorders or circadian rhythm sleep-wake disorders.The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assigned strengths based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.The following recommendations are intended as a guide for clinicians using actigraphy in evaluating patients with sleep disorders and circadian rhythm sleep-wake disorders, and only apply to the use of FDA-approved devices. Each recommendation statement is assigned a strength ("Strong" or "Conditional"). A "Strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "Conditional" recommendation (ie, "We suggest…") reflects a lower degree of certainty regarding the outcome and appropriateness of the patient-care strategy for all patients. The ultimate judgment regarding any specific care must be made by the treating clinician and the patient, taking into consideration the individual circumstances of the patient, available treatment options, and resources.1. We suggest that clinicians use actigraphy to estimate sleep parameters in adult patients with insomnia disorder. (Conditional).2. We suggest that clinicians use actigraphy in the assessment of pediatric patients with insomnia disorder. (Conditional).3. We suggest that clinicians use actigraphy in the assessment of adult patients with circadian rhythm sleep-wake disorder. (Conditional).4. We suggest that clinicians use actigraphy in the assessment of pediatric patients with circadian rhythm sleep-wake disorder. (Conditional).5. We suggest that clinicians use actigraphy integrated with home sleep apnea test devices to estimate total sleep time during recording (in the absence of alternative objective measurements of total sleep time) in adult patients suspected of sleep-disordered breathing. (Conditional).6. We suggest that clinicians use actigraphy to monitor total sleep time prior to testing with the Multiple Sleep Latency Test in adult and pediatric patients with suspected central disorders of hypersomnolence. (Conditional) We suggest that clinicians use actigraphy to estimate total sleep time in adult patients with suspected insufficient sleep syndrome. (Conditional).7. We recommend that clinicians not use actigraphy in place of electromyography for the diagnosis of periodic limb movement disorder in adult and pediatric patients. (Strong).

  View details for PubMedID 29991437

• Validation of minute-to-minute scoring for sleep and wake periods in a consumer wearable device compared to an actigraphy device Sleep Science and Practice Cheung, J., Zeitzer, J. M., Lu, H., Mignot, E. 2018

  View details for DOI 10.1186/s41606-018-0029-8

• Bidirectional associations of accelerometer-determined sedentary behavior and physical activity with reported time in bed: Women's Health Study. Sleep health Pettee Gabriel, K., Sternfeld, B., Shiroma, E. J., Pérez, A., Cheung, J., Lee, I. M. 2017; 3 (1): 49–55

  Abstract

  To examine the day-to-day, bidirectional associations of accelerometer-derived sedentary behavior and physical activity (PA) with reported time in bed in a large cohort of older women.Data are from 10086 Women's Health Study participants (aged 71.6 years; SD, 5.7) who agreed to wear an accelerometer and complete a diary for 7 consecutive days. Generalized linear (multilevel) models with repeated measures were used to examine the adjusted associations of the following: (1) reported time in bed with next-day accelerometer-determined counts and time spent sedentary and in light- and moderate-to-vigorous-intensity PA (MVPA) and (2) accelerometer estimates with reported time in bed that night, expressed as short (<7 hours), optimal (7-9 hours), and long (>9 hours) sleep.Across days, short sleep was associated with an average of 5500 (SE, 1352) higher accelerometer counts the following day but was also related to higher average sedentary (46.5 [SE, 1.5] minutes) and light-intensity PA (11.9 [SE, 1.2] minutes) than optimal sleep (all P<.001). Long sleep was associated with lower accelerometer counts, time spent sedentary and in light-intensity PA, and a reduced likelihood of engaging in ≥20 minutes of MVPA (all P<.001) than optimal sleep. Higher PA during the day (higher accelerometer counts and ≥20 minutes of accumulated MVPA) was associated with a reduced likelihood of reporting short or long sleep that night (all P<.001).Findings support the bidirectional associations of accelerometer-determined sedentary behavior and PA with reported time in bed in older women. Future studies are needed to confirm findings with sleep actigraphy in older women.

  View details for DOI 10.1016/j.sleh.2016.10.001

  View details for PubMedID 28346151

  View details for PubMedCentralID PMC5373487

• Central Nervous System Hypersomnias Sleep and Neurologic Disease Cheung, J., Ruoff, C., Mignot, E. Elsevier. 2017; 1: 141–166
• The Boom in Wearable Technology: Cause for Alarm or Just What is Needed to Better Understand Sleep? Sleep de Zambotti, M., Godino, J. G., Baker, F. C., Cheung, J., Patrick, K., Colrain, I. M. 2016; 39 (9): 1761-1762

  View details for DOI 10.5665/sleep.6108

  View details for PubMedID 27397564

  View details for PubMedCentralID PMC4989265

• Genetic basis of chronotype in humans: Insights from three landmark GWAS. Sleep Kalmbach, D. A., Schneider, L. D., Cheung, J., Bertrand, S. J., Kariharan, T., Pack, A. I., Gehrman, P. R. 2016

  Abstract

  Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related medical and psychiatric illnesses. Twin and family studies have shown that chronotype is a heritable trait, thus directing attention toward its genetic basis. Chronotype is influenced by a large number of genetic variants, making it a complex phenotype. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWASs), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes such as chronotype. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. Several genes previously unknown to influence chronotype were identified. The present review discusses findings of these three GWASs in the context of prior research. Replicated and non-replicated results across these GWASs are discussed along with explorations of methodological differences. Future directions in molecular science, model systems, and discovery of rare variants are discussed.

  View details for PubMedID 27855737

• gamma-Hydroxybutyric Acid-Induced Electrographic Seizures JOURNAL OF CLINICAL SLEEP MEDICINE Cheung, J., Lucey, B. P., Duntley, S. P., Darken, R. S. 2014; 10 (7): 811-812

  Abstract

  We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate.

  View details for DOI 10.5664/jcsm.3882

  View details for Web of Science ID 000341136100016

  View details for PubMedID 25024661

  View details for PubMedCentralID PMC4067447

• Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior PSYCHONEUROENDOCRINOLOGY Hammack, S. E., Cheung, J., Rhodes, K. M., Schutz, K. C., Falls, W. A., Braas, K. M., May, V. 2009; 34 (6): 833-843

  Abstract

  Exposure to chronic stress has been argued to produce maladaptive anxiety-like behavioral states, and many of the brain regions associated with stressor responding also mediate anxiety-like behavior. Pituitary adenylate cyclase activating polypeptide (PACAP) and its specific G protein-coupled PAC(1) receptor have been associated with many of these stress- and anxiety-associated brain regions, and signaling via this peptidergic system may facilitate the neuroplasticity associated with pathological affective states. Here we investigated whether chronic stress increased transcript expression for PACAP, PAC(1) receptor, brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB) in several nuclei. In rats exposed to a 7 days chronic variate stress paradigm, chronic stress enhanced baseline startle responding induced by handling and exposure to bright lights. Following chronic stress, quantitative transcript assessments of brain regions demonstrated dramatic increases in PACAP and PAC(1) receptor, BDNF, and TrkB receptor mRNA expression selectively in the dorsal aspect of the anterolateral bed nucleus of the stria terminalis (dBNST). Related vasoactive intestinal peptide (VIP) and VPAC receptor, and other stress peptide transcript levels were not altered compared to controls. Moreover, acute PACAP38 infusion into the dBNST resulted in a robust dose-dependent anxiogenic response on baseline startle responding that persisted for 7 days. PACAP/PAC(1) receptor signaling has established trophic functions and its coordinate effects with chronic stress-induced dBNST BDNF and TrkB transcript expression may underlie the maladaptive BNST remodeling and plasticity associated with anxiety-like behavior.

  View details for DOI 10.1016/j.psyneuen.2008.12.013

  View details for Web of Science ID 000266398800005

  View details for PubMedID 19181454

  View details for PubMedCentralID PMC2705919

• Comparative analysis of the paired immunoglobulin-like receptor (PILR) locus in six mammalian genomes: duplication, conversion, and the birth of new genes PHYSIOLOGICAL GENOMICS Wilson, M. D., Cheung, J., Martindale, D. W., Scherer, S. W., Koop, B. F. 2006; 27 (3): 201-218

  Abstract

  Manyaspects of the immune system are controlled by homologous cell surface receptors that mediate inhibitory and activating pathways. The paired immunoglobulin-like receptor (PILR) locus at 7q22 encodes both PILRA, an inhibitory receptor, and PILRB, its activating counterpart. Mouse Pilrb1 is a novel immune system regulator, and its ligand Cd99 participates in the recruitment of T-cells to inflamed tissue. We characterized the PILR locus in six mammalian genomes and investigated the structure and mRNA expression of human PILRB. Synteny at the PILR locus is conserved in the human, chimpanzee, dog, mouse and rat genomes. The absence of the PILR locus in opossum and chicken genomes suggests it arose after the divergence of placental and nonplacental mammals. In humans, a Williams-Beuren syndrome-related segmental duplication has created a complex chimeric transcript representing the predominantly expressed form of PILRB. Unlike PILRA, PILRB transcripts were detected in a wide variety of tissues including cells of the lymphoid lineage. In the mouse genome, a second activating gene, Pilrb2, and six pseudogenes were found. Extensive gene duplications in the rat genome have resulted in at least 27 Pilrb genes and or pseudogenes. Abundant gene duplication events involving novel CD99-related genes were also detected in the rat genome. In addition to duplication, we show that gene conversion has played a persistent role in the evolution of the PILR genes. Overall, we demonstrate that the PILR locus is dynamically evolving via multiple evolutionary mechanisms in several mammalian genomes.

  View details for DOI 10.1152/physiolgenomics.00284.2005

  View details for Web of Science ID 000242340100002

  View details for PubMedID 16926269

• Genomic analysis of five chromosome 7p deletion patients with Greig cephalopolysyndactyly syndrome (GCPS) EUROPEAN JOURNAL OF MEDICAL GENETICS Schwarzbraun, T., Windpassinger, C., Ofner, L., Vincent, J. B., Cheung, J., Scherer, S. W., Wagner, K., Kroise, P. M., Petek, E. 2006; 49 (4): 338-345

  Abstract

  Chromosomal deletions on chromosome 7p are associated with Greig cephalopolysyndactyly syndrome (GCPS, OMIM 175700) a syndrome affecting the development of the skull, face, and limbs. We have compared data from molecular cytogenetic and genetic analyses with clinical symptoms from five previously published GCPS deletion patients, including a pair of monozygotic twins. The genomic DNA of the probands and their parents, as well as the DNA from monoallelic cell lines of two patients, was analyzed using microsatellite markers. In some cases (e.g. where the microsatellite studies were uninformative) we also used fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BAC) probes. The fine mapping results of the deletions and genomic data from chromosome 7, were compared to the clinical symptoms. Common breakpoint sequences or mutation hotspots were not observed. Mutation screening for PGAM2, which is responsible for a form of myopathy with recessive inheritance, was performed in all patients. Loss of heterozygosity for known genes with dominant inheritance, such as the glucokinase gene (GCK), which, when mutated or haploinsufficient, is responsible for maturity-onset diabetes of the young, type II (MODY2, OMIM 125851), was identified and included in a genetic counseling of the patients' families.

  View details for DOI 10.1016/j.ejmg.2005.10.133

  View details for Web of Science ID 000239468500008

  View details for PubMedID 16829355

• Duplication and relocation of the functional DPY19L2 gene within low copy repeats BMC GENOMICS Carson, A. R., Cheung, J., Scherer, S. W. 2006; 7

  Abstract

  Low copy repeats (LCRs) are thought to play an important role in recent gene evolution, especially when they facilitate gene duplications. Duplicate genes are fundamental to adaptive evolution, providing substrates for the development of new or shared gene functions. Moreover, silencing of duplicate genes can have an indirect effect on adaptive evolution by causing genomic relocation of functional genes. These changes are theorized to have been a major factor in speciation.Here we present a novel example showing functional gene relocation within a LCR. We characterize the genomic structure and gene content of eight related LCRs on human Chromosomes 7 and 12. Two members of a novel transmembrane gene family, DPY19L, were identified in these regions, along with six transcribed pseudogenes. One of these genes, DPY19L2, is found on Chromosome 12 and is not syntenic with its mouse orthologue. Instead, the human locus syntenic to mouse Dpy19l2 contains a pseudogene, DPY19L2P1. This indicates that the ancestral copy of this gene has been silenced, while the descendant copy has remained active. Thus, the functional copy of this gene has been relocated to a new genomic locus. We then describe the expansion and evolution of the DPY19L gene family from a single gene found in invertebrate animals. Ancient duplications have led to multiple homologues in different lineages, with three in fish, frogs and birds and four in mammals.Our results show that the DPY19L family has expanded throughout the vertebrate lineage and has undergone recent primate-specific evolution within LCRs.

  View details for DOI 10.1186/1471-2164-7-45

  View details for Web of Science ID 000238291200001

  View details for PubMedID 16526957

• Murine segmental duplications are hot spots for chromosome and gene evolution GENOMICS Armengol, L., Marques-Bonet, T., Cheung, J., Khaja, R., Gonzalez, J. R., Scherer, S. W., Navarro, A., Estivill, X. 2005; 86 (6): 692-700

  Abstract

  Mouse and rat genomic sequences permit us to obtain a global view of evolutionary rearrangements that have occurred between the two species and to define hallmarks that might underlie these events. We present a comparative study of the sequence assemblies of mouse and rat genomes and report an enrichment of rodent-specific segmental duplications in regions where synteny is not preserved. We show that segmental duplications present higher rates of molecular evolution and that genes in rearranged regions have evolved faster than those located elsewhere. Previous studies have shown that synteny breakpoints between the mouse and the human genomes are enriched in human segmental duplications, suggesting a causative connection between such structures and evolutionary rearrangements. Our work provides further evidence to support the role of segmental duplications in chromosomal rearrangements in the evolution of the architecture of mammalian chromosomes and in the speciation processes that separate the mouse and the rat.

  View details for DOI 10.1016/j.ygeno.2005.08.008

  View details for Web of Science ID 000234396200008

  View details for PubMedID 16256303

• 'Fishing' out a long distance regulator of the sonic hedgehog gene associated with preaxial polydactyly. Pediatric research Cheung, J. 2003; 54 (5): 623-624

  View details for PubMedID 14578456

• Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements HUMAN MOLECULAR GENETICS Armengol, L., Pujana, M. A., Cheung, J., Scherer, S. W., Estivill, X. 2003; 12 (17): 2201-2208

  Abstract

  The sequence of the mouse genome allows one to compare the conservation of synteny between the human and mouse genome and exploration of regions that might have been involved in major rearrangements during the evolution of these two species (evolutionary genome rearrangements). Recent segmental duplications (or duplicons) are paralogous DNA sequences with high sequence identity that account for about 3.5-5% of the human genome and have emerged during the past approximately 35 million years of evolution. These regions are susceptible to illegitimate recombination leading to rearrangements that result in genomic disorders or genomic mutations. A catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported. The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome and that regions flanked by segmental duplications are often polymorphic. We have compared the human and mouse genome sequences and demonstrate here that recent segmental duplications correlate with breaks of synteny between these two species. We also observed that nine primary regions involved in human genomic disorders show changes in the order or the orientation of mouse/human synteny segments, were often flanked by segmental duplications in the human sequence. We found that 53% of all evolutionary rearrangement breakpoints associate with segmental duplications, as compared with 18% expected in a random location of breaks along the chromosome (P<0.0001). Our data suggest that segmental duplications have participated in the recent evolution of the human genome, as driving forces for evolutionary rearrangements, chromosome structure polymorphisms and genomic disorders.

  View details for DOI 10.1093/hmg/ddg223

  View details for Web of Science ID 000185321300011

  View details for PubMedID 12915466

• Genescript: DNA sequence annotation pipeline BIOINFORMATICS Hudek, A. K., Cheung, J., Boright, A. P., Scherer, S. W. 2003; 19 (9): 1177-1178

  Abstract

  Genescript uses a number of publicly available analysis programs to annotate a DNA sequence. It provides an integrated display of results from each program, and includes an evidence-based scoring system that gives informative summaries of predicted gene models.Genescript is available for download from http:://tcag.bioinfo.sickkids.on.ca/genescript/

  View details for DOI 10.1093/bioinformatics/btg134

  View details for Web of Science ID 000183528300019

  View details for PubMedID 12801881

• GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome BLOOD Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W., Zipursky, A. 2003; 101 (11): 4301-4304

  Abstract

  Children with constitutional trisomy 21 (Down syndrome) have an approximately 500-fold increased risk of developing acute megakaryoblastic leukemia (AMKL), a form of acute myeloid leukemia. Unique to newborn infants with Down syndrome is a transient leukemia (TL), also referred to as transient myeloproliferative syndrome, that undergoes spontaneous remission in the majority of cases but in approximately 20% is followed by AMKL later in life. Recently mutations of the gene encoding the hematopoietic transcription factor GATA1 were shown to be specific for AMKL of Down syndrome. Here, we demonstrate that GATA1 mutations are present in blasts of TL and show the identical GATA1 mutation in sequential samples collected from a patient during TL and subsequent AMKL. These findings suggest a model of malignant transformation in Down syndrome AMKL in which GATA1 mutations are an early event and AMKL arises from latent TL clones following initial apparent remission.

  View details for DOI 10.1182/blood-2003-01-0013

  View details for Web of Science ID 000183072800021

  View details for PubMedID 12586620

• Identification of a novel lipase gene mutated in Ipd mice with hypertriglyceridemia and associated with dyslipidemia in humans HUMAN MOLECULAR GENETICS Wen, X. Y., Hegele, R. A., Wang, J., Wang, D. Y., Cheung, J., Wilson, M., Yahyapour, M., Bai, Y., Zhuang, L. H., Skaug, J., Young, T. K., Connelly, P. W., Koop, B. F., TSUI, L. C., Stewart, A. K. 2003; 12 (10): 1131-1143

  Abstract

  Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.

  View details for DOI 10.1093/hmg/ddg124

  View details for Web of Science ID 000182950200006

  View details for PubMedID 12719377

• Human chromosome 7: DNA sequence and biology SCIENCE Scherer, S. W., Cheung, J., Macdonald, J. R., Osborne, L. R., Nakabayashi, K., Herbrick, J. A., Carson, A. R., Parker-Katiraee, L., Skaug, J., Khaja, R., Zhang, J. J., Hudek, A. K., Li, M., Haddad, M., Duggan, G. E., Fernandez, B. A., Kanematsu, E., Gentles, S., Christopoulos, C. C., Choufani, S., Kwasnicka, D., Zheng, X. Q., Lai, Z. W., Nusskern, D., Zhang, Q., Gu, Z. P., Lu, F., Zeesman, S., Nowaczyk, M. J., Teshima, I., Chitayat, D., Shuman, C., Weksberg, R., Zackai, E. H., Grebe, T. A., Cox, S. R., Kirkpatrick, S. J., Rahman, N., Friedman, J. M., Heng, H. H., Pelicci, P. G., Lo-Coco, F., Belloni, E., Shaffer, L. G., Pober, B., Morton, C. C., Gusella, J. F., Bruns, G. A., Korf, B. R., Quade, B. J., Ligon, A. H., Ferguson, H., Higgins, A. W., Leach, N. T., Herrick, S. R., Lemyre, E., Farra, C. G., Kim, H. G., Summers, A. M., Gripp, K. W., Roberts, W., Szatmari, P., Winsor, E. J., Grzeschik, K. H., Teebi, A., Minassian, B. A., Kere, J., Armengol, L., Pujana, M. A., Estivill, X., Wilson, M. D., Koop, B. F., Tosi, S., Moore, G. E., Boright, A. P., Zlotorynski, E., Kerem, B., Kroisel, P. M., Petek, E., Oscier, D. G., Mould, S. J., Dohner, H., Dohner, K., Rommens, J. M., Vincent, J. B., Venter, J. C., Li, P. W., Mural, R. J., Adams, M. D., TSUI, L. C. 2003; 300 (5620): 767-772

  Abstract

  DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.

  View details for DOI 10.1126/science.1083423

  View details for Web of Science ID 000182579800041

  View details for PubMedID 12690205

• Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions HUMAN MOLECULAR GENETICS Gimelli, G., Pujana, M. A., Patricelli, M. G., Russo, S., Giardino, D., Larizza, L., Cheung, J., Armengol, L., Schinzel, A., Estivill, X., Zuffardi, O. 2003; 12 (8): 849-858

  Abstract

  Parental submicroscopic genomic inversions have recently been demonstrated to be present in several genomic disorders. These inversions are genomic polymorphisms that facilitate misalignment and abnormal recombination between flanking segmental duplications. Angelman syndrome (AS; MIM 105830) is associated with specific abnormalities of chromosome 15q11-q13, with about 70% of cases being mother-of-origin 4 Mb deletions. We present here evidence that some mothers of AS patients with deletions of the 15q11-q13 region have a heterozygous inversion involving the region that is deleted in the affected offspring. The inversion was detected in the mothers of four of six AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion, but not in seven mothers of AS due to paternal uniparental disomy (UPD) 15. We have identified variable inversion breakpoints within BP segmental duplications in the inverted AS mothers, as well as in AS deleted patients. Interestingly, the BP2-BP3 region is inverted in the mouse draft genome sequence with respect to the human draft sequence. The BP2-BP3 chromosome 15q11-q13 inversion was detected in four of 44 subjects (9%) of the general population (P<0.004). The BP2/3 inversion should be an intermediate estate that facilitates the occurrence of 15q11-q13 BP2/3 deletions in the offspring.

  View details for DOI 10.1093/hmg/ddg101

  View details for Web of Science ID 000182393700005

  View details for PubMedID 12668608

• Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence GENOME BIOLOGY Cheung, J., Estivill, X., Khaja, R., Macdonald, J. R., Lau, K., TSUI, L. C., Scherer, S. W. 2003; 4 (4)

  Abstract

  Previous studies have suggested that recent segmental duplications, which are often involved in chromosome rearrangements underlying genomic disease, account for some 5% of the human genome. We have developed rapid computational heuristics based on BLAST analysis to detect segmental duplications, as well as regions containing potential sequence misassignments in the human genome assemblies.Our analysis of the June 2002 public human genome assembly revealed that 107.4 of 3,043.1 megabases (Mb) (3.53%) of sequence contained segmental duplications, each with size equal or more than 5 kb and 90% identity. We have also detected that 38.9 Mb (1.28%) of sequence within this assembly is likely to be involved in sequence misassignment errors. Furthermore, we have identified a significant subset (199,965 of 2,327,473 or 8.6%) of single-nucleotide polymorphisms (SNPs) in the public databases that are not true SNPs but are potential paralogous sequence variants.Using two distinct computational approaches, we have identified most of the sequences in the human genome that have undergone recent segmental duplications. Near-identical segmental duplications present a major challenge to the completion of the human genome sequence. Potential sequence misassignments detected in this study would require additional efforts to resolve.

  View details for Web of Science ID 000182696200007

  View details for PubMedID 12702206

• Recent segmental and gene duplications in the mouse genome GENOME BIOLOGY Cheung, J., Wilson, M. D., Zhang, J. J., Khaja, R., Macdonald, J. R., Heng, H. H., Koop, B. F., Scherer, S. W. 2003; 4 (8)

  Abstract

  The high quality of the mouse genome draft sequence and its associated annotations are an invaluable biological resource. Identifying recent duplications in the mouse genome, especially in regions containing genes, may highlight important events in recent murine evolution. In addition, detecting recent sequence duplications can reveal potentially problematic regions of the genome assembly. We use BLAST-based computational heuristics to identify large (>/= 5 kb) and recent (>/= 90% sequence identity) segmental duplications in the mouse genome sequence. Here we present a database of recently duplicated regions of the mouse genome found in the mouse genome sequencing consortium (MGSC) February 2002 and February 2003 assemblies.We determined that 33.6 Mb of 2,695 Mb (1.2%) of sequence from the February 2003 mouse genome sequence assembly is involved in recent segmental duplications, which is less than that observed in the human genome (around 3.5-5%). From this dataset, 8.9 Mb (26%) of the duplication content consisted of 'unmapped' chromosome sequence. Moreover, we suspect that an additional 18.5 Mb of sequence is involved in duplication artifacts arising from sequence misassignment errors in this genome assembly. By searching for genes that are located within these regions, we identified 675 genes that mapped to duplicated regions of the mouse genome. Sixteen of these genes appear to have been duplicated independently in the human genome. From our dataset we further characterized a 42 kb recent segmental duplication of Mater, a maternal-effect gene essential for embryogenesis in mice.Our results provide an initial analysis of the recently duplicated sequence and gene content of the mouse genome. Many of these duplicated loci, as well as regions identified to be involved in potential sequence misassignment errors, will require further mapping and sequencing to achieve accuracy. A Genome Browser database was set up to display the identified duplication content presented in this work. This data will also be relevant to the growing number of investigators who use the draft genome sequence for experimental design and analysis.

  View details for Web of Science ID 000184536400007

  View details for PubMedID 12914656

• The RAY1/ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript system GENOMICS Vincent, J. B., Petek, E., Thevarkunnel, S., Kolozsvari, D., Cheung, J., Patel, M., Scherer, S. W. 2002; 80 (3): 283-294

  Abstract

  We recently identified a novel gene, RAY1 (FAM4A1), which spans a translocation breakpoint at 7q31 in a patient with autism. This gene has more recently been reported to be a suppressor of tumorigenicity, ST7, although controversy surrounds this observation because subsequent reports have failed to corroborate these findings. Our further analysis of this locus reveals that it is composed of a multigene system that includes two noncoding sense strand genes (ST7OT3 and ST7OT4) that overlap with many alternative forms of the coding RAY1/ST7 transcript, and two noncoding genes on the antisense strand (ST7OT1 and ST7OT2). RAY1/ST7 was determined to have at least three different 5' exons with alternative start codons, one of which seems to be used almost exclusively in the brain. We have also identified a third alternative 3' end of RAY1/ST7 that uses exons from ST7OT3. ST7OT3 spans from intron 10 to exon 14 of RAY1/ST7 and includes several exons. ST7OT4 has at least seven exons and is transcribed on the sense strand between RAY1/ST7 exon 1 and a tropomyosin-like sequence, TPM3L2. ST7OT1 overlaps with the RAY1/ST7 exon 1 and promoter. ST7OT2 spans from RAY1/ST7 intron 9 to intron 1, and has multiple isoforms. We screened the exons of RAY1/ST7 and ST7OT1-3 for sequence variants in 90 unrelated autism probands and identified several rare variants, including a Ile361Val substitution. Although these variants were not observed in a control population, it is unclear whether they contribute to the autistic phenotype. We postulate that the apparent noncoding genes at the RAY1/ST7 locus may be regulatory RNAs. The RAY1/ST7 may generate at least 18 possible isoforms, with many more arising if other sense-strand exons from ST7OT3 and ST7 OT4 are used in a selective and possibly tissue-specific manner.

  View details for DOI 10.1006/geno.2002.6835

  View details for Web of Science ID 000177774200007

  View details for PubMedID 12213198

• Chromosomal regions containing high-density and ambiguously mapped putative single nucleotide polymorphisms (SNPs) correlate with segmental duplications in the human genome HUMAN MOLECULAR GENETICS Estivill, X., Cheung, J., Pujana, M. A., Nakabayashi, K., Scherer, S. W., TSUI, L. C. 2002; 11 (17): 1987-1995

  Abstract

  We have explored the National Center for Biotechnology Information (NCBI) single nucleotide polymorphisms (SNPs) database for a correlation between the density of putative SNPs, as well as SNPs that map to different chromosomal locations (ambiguously mapped SNPs), and segmental duplications of DNA in chromosome regions involved in genomic disorders. A high density of SNPs (14.4 and 12.4 SNPs per kb) was detected in the low copy repeats (LCRs) responsible for the chromosome 17p12 duplication and deletion that cause peripheral neuropathies. None of the SNPs at the PMP22 gene were ambiguously mapped, but 93% of the SNPs at LCRs mapped on both LCR copies, indicating that they are in fact variants in paralogous sequences. Similarly, a high SNP density was found in the LCR regions flanking the neurofibromatosis type 1 (NF1) gene, with 80% of SNPs mapping on both LCR copies. A high density of SNPs was found within LCR sequences involved in the deletions that mediate contiguous gene syndromes on chromosomes 7q11, 15q11-q13 and 22q11. We have analyzed the whole sequence of chromosome 22, which contains 14% of ambiguously mapped SNPs, and have found a good correlation between these SNPs and segmental duplications detected by BLAST analysis. We have identified several segments of ambiguously mapped SNPs, four corresponding to LCRs involved in the chromosome 22q11 microdeletion syndromes. Our data indicate that most SNPs in LCR segments are in fact paralogous sequence variants (PSVs), and suggest that a significant proportion of the SNPs in the NCBI database correspond to PSVs within segmental duplications of the human genome sequence.

  View details for Web of Science ID 000177356600008

  View details for PubMedID 12165560

• Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex JOURNAL OF NEUROCHEMISTRY Khabazian, I., Bains, J. S., Williams, D. E., Cheung, J., Wilson, J. M., Pasqualotto, B. A., Pelech, S. L., Andersen, R. J., Wang, Y. T., Liu, L., Nagai, A., Kim, S. U., Craig, U. K., Shaw, C. A. 2002; 82 (3): 516-528

  Abstract

  The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.

  View details for Web of Science ID 000177027400007

  View details for PubMedID 12153476

• A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease GENOMICS Xiong, H. Q., Chen, Y. X., Yi, Y. J., Tsuchiya, K., Moeckel, G., Cheung, J., Liang, D., Tham, K., Xu, X. H., Chen, X. Z., Pei, Y., Zhao, Z. Z., Wu, G. Q. 2002; 80 (1): 96-104

  Abstract

  Autosomal recessive polycystic kidney disease (ARPKD) is a common hereditary renal cystic disease in infants and children. By genetic linkage analyses, the gene responsible for this disease, termed polycystic kidney and hepatic disease 1 (PKHD1), was mapped on human chromosome 6p21.1-p12, and has been further localized to a 1-cM genetic interval flanked by the D6S1714/D6S243 (telomeric) and D6S1024 (centromeric) markers. We recently identified a novel gene in this genetic interval from kidney cDNA, using cloning strategies. The gene PKHD1 (PKHD1-tentative) encodes a novel 3396-amino-acid protein with no apparent homology with any known proteins. We named its gene product "tigmin" because it contains multiple TIG domains, which usually are seen in proteins containing immunoglobulin-like folds. PKHD1 encodes an 11.6-kb transcript and is composed of 61 exons spanning an approximately 365-kb genomic region on chromosome 6p12-p11.2 adjacent to the marker D6S1714. Northern blot analyses demonstrated that the gene has discrete bands with one peak signal at approximately 11 kb, indicating that PKHD1 is likely to have multiple alternative transcripts. PKHD1 is highly expressed in adult and infant kidneys and weakly expressed in liver in northern blot analysis. This expression pattern parallels the tissue involvement observed in ARPKD. In situ hybridization analysis further revealed that the expression of PKHD1 in the kidney is mainly localized to the epithelial cells of the collecting duct, the specific tubular segment involved in cyst formation in ARPKD. These features of PKHD1 make it a strong positional candidate gene for ARPKD.

  View details for DOI 10.1006/geno.2002.6802

  View details for Web of Science ID 000176495300015

  View details for PubMedID 12079288

• A role for common fragile site induction in amplification of human oncogenes CANCER CELL Hellman, A., Zlotorynski, E., Scherer, S. W., Cheung, J., Vincent, J. B., Smith, D. I., Trakhtenbrot, L., Kerem, B. 2002; 1 (1): 89-97

  Abstract

  Oncogene amplification is an important process in human tumorigenesis, but its underlying mechanism is currently unknown. Cytogenetic analysis indicates that amplification of drug-selected genes in rodent cells is driven by recurrent breaks within chromosomal common fragile sites (CFSs), via the breakage-fusion-bridge (BFB) mechanism. Here we show that BFB cycles drive the intrachromosomal amplification of the MET oncogene in a human gastric carcinoma. Our molecular evidence includes a "ladder-like" structure and inverted repeat organization of the MET amplicons. Furthermore, we show that the breakpoints, setting the centromeric amplicon boundaries, are within the CFS FRA7G region. Upon replication stress, this region showed perturbed chromatin organization, predisposing it to breakage. Thus, in vivo induction of CFSs can play an important role in human oncogenesis.

  View details for Web of Science ID 000178347800013

  View details for PubMedID 12086891

• Vanishing websites are the weakest link NATURE Cheung, J. 2001; 414 (6859): 15-15

  View details for Web of Science ID 000171898900014

  View details for PubMedID 11689913

• Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31 GENOMICS Cheung, J., Petek, E., Nakabayashi, K., TSUI, L. C., Vincent, J. B., Scherer, S. W. 2001; 78 (1-2): 7-11

  Abstract

  Human chromosome 7q31 contains putative susceptibility loci for autism (AUTS1) and speech and language disorder (SPCH1). We report here the identification and characterization of a novel gene encoding cortactin-binding protein-2 (CORTBP2), which is located 45 kb telomeric to the cystic fibrosis transmembrane conductance regulator gene (CFTR) at 7q31.3. The full-length (5975-bp) gene was isolated and found to be composed of 23 exons encompassing 170 kb of DNA. In addition to being a positional candidate for AUTS1, CORTBP2 was expressed at highest levels in the brain, as shown by northern blot analysis. Subsequent mutation analysis of CORTBP2 in 90 autistic patients identified two polymorphisms, including a leucine to valine change caused by a T to G substitution in exon 15. However, comparison of allele frequencies between autistic and control populations (n=96) showed no significant difference, suggesting that this variant is not a susceptibility factor for autism.

  View details for DOI 10.1006/geno.2001.6651

  View details for Web of Science ID 000172121700003

  View details for PubMedID 11707066

• Discovery of the human genome sequence in the public and private databases CURRENT BIOLOGY Scherer, S. W., Cheung, J. 2001; 11 (20): R808-R811

  Abstract

  Genomes: Much heat has been generated in discussions about the key human genome sequence databases, generated by the Human Genome Project and Celera, and what specific features each offers genome researchers. Stephen W. Scherer and Joseph Cheung, who are intense users of both, offer a personal assessment of the developing contents.

  View details for Web of Science ID 000171651700002

  View details for PubMedID 11676931

• Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome AMERICAN JOURNAL OF HUMAN GENETICS Petek, E., Windpassinger, C., Vincent, J. B., Cheung, J., Boright, A. P., Scherer, S. W., Kroisel, P. M., Wagner, K. 2001; 68 (4): 848-858

  Abstract

  Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. We identified a male patient with GTS and other anomalies. It was determined that he carried a de novo duplication of the long arm of chromosome 7 [46,XY,dup(7)(q22.1-q31.1)]. Further molecular analysis revealed that the duplication was inverted. The distal chromosomal breakpoint occurred between the two genetic markers D7S515 and D7S522, which define a region previously shown to be disrupted in a familiar case of GTS. Yeast and bacterial artificial chromosome clones spanning the breakpoints were identified by means of FISH analysis. To further characterize the distal breakpoint for a role in GTS, we performed Southern blot hybridization analysis and identified a 6.5-kb SacI junction fragment in the patient's genomic DNA. The DNA sequence of this fragment revealed two different breaks in 7q31 within a region of approximately 500 kb. IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. The cDNA of the human IMMP2L gene was cloned, and analysis of the complete 1,522-bp transcript revealed that it encompassed six exons spanning 860 kb. The possible role of IMMP2L and several other candidate genes within the region of chromosomal rearrangement, including NRCAM, Leu-Rch Rep, and Reelin, is discussed. The 7q31 breakpoint interval has also been implicated in other neuropsychiatric diseases that demonstrate some clinical overlap with GTS, including autism and speech-language disorder.

  View details for Web of Science ID 000167666000006

  View details for PubMedID 11254443