Bio

Bio


Dr. Gomez-Ospina was born and raised in Medellin, Colombia. She began her undergraduate studies in petroleum engineering at the Universidad Nacional de Colombia before moving to Colorado. She double majored at the University of Colorado Boulder, completing her bachelor’s degree in Molecular Cellular and Developmental Biology as well as Biochemistry. She graduated summa cum laude and wrote an honors thesis entitled “Role of the quiescent center in the regeneration of the root cap in Zea Mays.” She then completed her combined MD, PhD at Stanford Medical School, where her PhD work focused on understanding the novel functions of voltage-gated calcium channels. Her PhD thesis, “The calcium channel CACNA1C gene: multiple proteins, diverse functions,” was published in Cell. After completion of her dual degrees, she did her preliminary year in internal medicine at Santa Barbara Cottage hospital before starting residency in Dermatology at Johns Hopkins Hospital. She completed residency in Medical Genetics at Stanford Hospital and clinics.

Her post-doctoral research was with Dr. Matthew Porteus in Pediatric Stem Cell transplantation, where she began to develop genome editing-based strategies in stem cells as a therapies for metabolic diseases. She is currently an instructor in the Department of Pediatrics. For her clinical practice she sees patients with suspected genetic disorders, and is also in charge of the enzyme replacement service for lysosomal storage disorders at Lucile Packard Children’s hospital. She has been the lead author in research studies in The New England Journal of Medicine, Cell, Nature Communications, and American Journal of Medical Genetics.

Clinical Focus


  • Clinical Genetics

Academic Appointments


Honors & Awards


  • Young Investigator Award, 14th annual WORLDSymposium on lysosomal storage diseases (2018)
  • Mentored Clinical Scientist Research Career Development Award (K08), NIH, National Institute of Neurological Diseases and Stroke (2017-2022)
  • Center of Excellence in Diversity in Medical Education Fellowship, Center of Excellence in Diversity in Medical Education (COEDME), Stanford Medicine (2016)
  • Tashia and John Morgridge Endowed Postdoctoral Fellow in Pediatric Translational Medicine, Child Health Research Institute (2015-2016)
  • Mead Johnson Travel Award. Novel form of neonatal cholestasis due to mutations in FXR, Western Society of Pediatric Research. Carmel, CA (2015)
  • Mead Johnson Travel Award. Respiratory involvement in Costello syndrome, Western Society of Pediatric Research. Carmel, CA (2014)
  • Summa cum laude and distinction in Molecular, Cellular and Developmental Biology, University of Colorado at Boulder (1999)

Professional Education


  • Board Certification: Clinical Genetics, American Board of Medical Genetics and Genomics (2015)
  • Residency:Stanford Hospital and Clinics (2015) CA
  • Residency:Johns Hopkins Hospital (2013) MD
  • Internship:Santa Barbara Cottage Hospital (2012) CA
  • Medical Education:Stanford University Medical School (2011) CA

Community and International Work


  • Fiesta Educativa, Mayfair Community Center, San Jose

    Topic

    Sindrome de Down

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Dr. Gomez-Ospina is a physician scientist and medical geneticist with a strong interest in the diagnosis and management of genetic diseases.

1) Lysosomal storage diseases:
Her research program is on developing better therapies for a large class of neurodegenerative diseases in children known as lysosomal storage disorders. Her current focus is on developing genome editing of hematopoietic stem cells as a therapeutic approach for these diseases beginning with Mucopolysaccharidosis type 1 and Gaucher disease. She established a genetic approach where therapeutic proteins can be targeted to a single well-characterized place in the genome known as a safe harbor. This approach constitutes a flexible, “one size fits all” approach that is independent of specific genes and mutations. This strategy, in which the hematopoietic system is commandeered to express and deliver therapeutic proteins to the brain can potentially change the current approaches to treating childhood neurodegenerative diseases and pave the way for alternative therapies for adult neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease


2) Point of care ammonia testing
She also works in collaboration with other researchers at Stanford to develop point-of-care testing for serum ammonia levels. Such device will greatly improve the quality of life of children and families with metabolic disorders with hyperammonemia.

3) Gene discovery
Dr Gomez-Ospina lead a multi-institutional collaboration resulting in the discovery of a novel genetic cause of neonatal and infantile cholestatic liver disease. She collaborated in the description of two novel neurologic syndromes caused by mutations in DYRK1 and CHD4.

Teaching

2018-19 Courses


Publications

All Publications


  • Gene Editing on Center Stage TRENDS IN GENETICS Bak, R. O., Gomez-Ospina, N., Porteus, M. H. 2018; 34 (8): 600–611

    Abstract

    Smithies et al. (1985) and Jasin and colleagues (1994) provided proof of concept that homologous recombination (HR) could be applied to the treatment of human disease and that its efficiency could be improved by the induction of double-strand breaks (DSBs). A key advance was the discovery of engineered nucleases, such as zinc-finger nucleases (ZFNs) and transcription activator-like (TAL) effector nucleases (TALENs), that can generate site-specific DSBs. The democratization and widespread use of genome editing was enabled by the discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system. While genome editing using ZFNs and TALENs has already reached clinical trials, the pace at which genome editing enters human trials is bound to accelerate in the next several years with multiple promising preclinical studies heralding cures for monogenic diseases that are currently difficult to manage or even incurable. Here we review recent advances and current limitations and discuss the path forward using genome editing to understand, treat, and cure genetic diseases.

    View details for DOI 10.1016/j.tig.2018.05.004

    View details for Web of Science ID 000438885900006

    View details for PubMedID 29908711

  • Engineering the Hematopoietic System for Lysosomal Storage Disorders: Correction of Mucopolysaccharidosis Type I Using Genome-Edited, Human Hematopoietic Stem and Progenitor Cells Gomez-Ospina, N., Scharenberg, S., Mostrel, N., Mantri, S., Nicolas, C., Porteus, M. M. CELL PRESS. 2018: 310–11
  • Engineering blood stem cells for autologous transplants for lysosomal diseases: Correction of mucopolysaccharidosis type I using genome-edited hematopoietic stem and progenitor cells Gomez-Ospina, N., Scharenberg, S. G., Mantri, S., Nicolas, C., Bak, R. O., Porteus, M. H. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2018: S54–S55
  • A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nature medicine Vakulskas, C. A., Dever, D. P., Rettig, G. R., Turk, R., Jacobi, A. M., Collingwood, M. A., Bode, N. M., McNeill, M. S., Yan, S., Camarena, J., Lee, C. M., Park, S. H., Wiebking, V., Bak, R. O., Gomez-Ospina, N., Pavel-Dinu, M., Sun, W., Bao, G., Porteus, M. H., Behlke, M. A. 2018; 24 (8): 1216–24

    Abstract

    Translation of the CRISPR-Cas9 system to human therapeutics holds high promise. However, specificity remains a concern especially when modifying stem cell populations. We show that existing rationally engineered Cas9 high-fidelity variants have reduced on-target activity when using the therapeutically relevant ribonucleoprotein (RNP) delivery method. Therefore, we devised an unbiased bacterial screen to isolate variants that retain activity in the RNP format. Introduction of a single point mutation, p.R691A, in Cas9 (high-fidelity (HiFi) Cas9) retained the high on-target activity of Cas9 while reducing off-target editing. HiFi Cas9 induces robust AAV6-mediated gene targeting at five therapeutically relevant loci (HBB, IL2RG, CCR5, HEXB, and TRAC) in human CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as primary T cells. We also show that HiFi Cas9 mediates high-level correction of the sickle cell disease (SCD)-causing p.E6V mutation in HSPCs derived from patients with SCD. We anticipate that HiFi Cas9 will have wide utility for both basic science and therapeutic genome-editing applications.

    View details for DOI 10.1038/s41591-018-0137-0

    View details for PubMedID 30082871

  • Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. American journal of human genetics Danhauser, K., Alhaddad, B., Makowski, C., Piekutowska-Abramczuk, D., Syrbe, S., Gomez-Ospina, N., Manning, M. A., Kostera-Pruszczyk, A., Krahn-Peper, C., Berutti, R., Kovács-Nagy, R., Gusic, M., Graf, E., Laugwitz, L., Röblitz, M., Wroblewski, A., Hartmann, H., Das, A. M., Bültmann, E., Fang, F., Xu, M., Schatz, U. A., Karall, D., Zellner, H., Haberlandt, E., Feichtinger, R. G., Mayr, J. A., Meitinger, T., Prokisch, H., Strom, T. M., Płoski, R., Hoffmann, G. F., Pronicki, M., Bonnen, P. E., Morlot, S., Haack, T. B. 2018; 103 (5): 817–25

    Abstract

    ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.

    View details for DOI 10.1016/j.ajhg.2018.10.005

    View details for PubMedID 30401461

  • Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain : a journal of neurology Alcantara, D., Timms, A. E., Gripp, K., Baker, L., Park, K., Collins, S., Cheng, C., Stewart, F., Mehta, S. G., Saggar, A., Sztriha, L., Zombor, M., Caluseriu, O., Mesterman, R., Van Allen, M. I., Jacquinet, A., Ygberg, S., Bernstein, J. A., Wenger, A. M., Guturu, H., Bejerano, G., Gomez-Ospina, N., Lehman, A., Alfei, E., Pantaleoni, C., Conti, V., Guerrini, R., Moog, U., Graham, J. M., Hevner, R., Dobyns, W. B., O'Driscoll, M., Mirzaa, G. M. 2017; 140 (10): 2610–22

    Abstract

    Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

    View details for DOI 10.1093/brain/awx203

    View details for PubMedID 28969385

  • Arylsulfatase A Deficiency Gomez-Ospina, N. GeneReviews® [Internet].. 2017
  • A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. American journal of medical genetics. Part A Crapster, J. A., Hudgins, L., Chen, J. K., Gomez-Ospina, N. 2017

    Abstract

    Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.

    View details for DOI 10.1002/ajmg.a.38415

    View details for PubMedID 28884880

  • Molecular and clinical spectra of FBXL4 deficiency. Human mutation El-Hattab, A. W., Dai, H., Almannai, M., Wang, J., Faqeih, E. A., Al Asmari, A., Saleh, M. A., Elamin, M. A., Alfadhel, M., Alkuraya, F. S., Hashem, M., Aldosary, M. S., Almass, R., Almutairi, F. B., Alsagob, M., Al-Owain, M., Al-Sharfa, S., Al-Hassnan, Z. N., Al Rahbeeni, Z., Al-Muhaizea, M. A., Makhseed, N., Foskett, G. K., Stevenson, D. A., Gomez-Ospina, N., Lee, C., Boles, R. G., Schrier Vergano, S. A., Wortmann, S. B., Sperl, W., Opladen, T., Hoffmann, G. F., Hempel, M., Prokisch, H., Alhaddad, B., Mayr, J. A., Chan, W., Kaya, N., Wong, L. C. 2017

    Abstract

    F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.23341

    View details for PubMedID 28940506

  • Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. Journal of inherited metabolic disease Gomez-Ospina, N., Scott, A. I., Oh, G. J., Potter, D., Goel, V. V., Destino, L., Baugh, N., Enns, G. M., Niemi, A., Cowan, T. M. 2016; 39 (6): 821-829

    Abstract

    Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.

    View details for PubMedID 27488560

  • De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms AMERICAN JOURNAL OF HUMAN GENETICS Weiss, K., Terhal, P. A., Cohen, L., Bruccoleri, M., Irving, M., Martinez, A. F., Rosenfeld, J. A., Machol, K., Yang, Y., Liu, P., Walkiewicz, M., Beuten, J., Gomez-Ospina, N., Haude, K., Fong, C., Enns, G. M., Bernstein, J. A., Fan, J., Gotway, G., Ghorbani, M., van Gassen, K., Monroe, G. R., van Haaften, G., Basel-Vanagaite, L., Yang, X., Campeau, P. M., Muenke, M. 2016; 99 (4): 934-941

    Abstract

    Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.

    View details for DOI 10.1016/j.ajhg.2016.08.001

    View details for Web of Science ID 000385333700014

    View details for PubMedID 27616479

  • Respiratory System Involvement in Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gomez-Ospina, N., Kuo, C., Ananth, A. L., Myers, A., Brennan, M., Stevenson, D. A., Bernstein, J. A., Hudgins, L. 2016; 170 (7): 1849-1857

    Abstract

    Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37655

    View details for Web of Science ID 000379948000019

    View details for PubMedID 27102959

  • Clinical, cytogenetic, and molecular outcomes in a series of 66 patients with Pierre Robin sequence and literature review: 22q11.2 deletion is less common than other chromosomal anomalies. American journal of medical genetics. Part A Gomez-Ospina, N., Bernstein, J. A. 2016; 170 (4): 870-880

    Abstract

    Pierre Robin sequence (PRS) is an important craniofacial anomaly that can be seen as an isolated finding or manifestation of multiple syndromes. 22q11.2 deletion and Stickler syndrome are cited as the two most common conditions associated with PRS, but their frequencies are debated. We performed a retrospective study of 66 patients with PRS and reviewed their genetic testing, diagnoses, and clinical findings. The case series is complemented by a comprehensive literature review of the nature and frequency of genetic diagnosis in PRS. In our cohort 65% of patients had associated anomalies; of these, a genetic diagnosis was established in 56%. Stickler syndrome was the most common diagnosis, comprising approximately 11% of all cases, followed by Treacher Collins syndrome (9%). The frequency of 22q11.2 deletion was 1.5%. Chromosome arrays, performed for 72% of idiopathic PRS with associated anomalies, revealed two cases of 18q22→qter deletion, a region not previously reported in association with PRS. A review of the cytogenetic anomalies identified in this population supports an association between the 4q33-qter, 17q24.3, 2q33.1, and 11q23 chromosomal loci and PRS. We found a low frequency of 22q11.2 deletion in PRS, suggesting it is less commonly implicated in this malformation. Our data also indicate a higher frequency of cytogenetic anomalies in PRS patients with associated anomalies, and a potential new link with the 18q22→qter locus. The present findings underscore the utility of chromosomal microarrays in cases of PRS with associated anomalies and suggest that delaying testing for apparently isolated cases should be considered. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37538

    View details for PubMedID 26756138

  • Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature communications Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M., Kim, K. H., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., Eng, C. M., Yang, Y., Washington, G. C., Porteus, M. H., Berquist, W. E., Kambham, N., Singh, R. J., Xia, F., Enns, G. M., Moore, D. D. 2016; 7: 10713-?

    Abstract

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

    View details for DOI 10.1038/ncomms10713

    View details for PubMedID 26888176

  • DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies EUROPEAN JOURNAL OF HUMAN GENETICS Ji, J., Lee, H., Argiropoulos, B., Dorrani, N., Mann, J., Martinez-Agosto, J. A., Gomez-Ospina, N., Gallant, N., Bernstein, J. A., Hudgins, L., Slattery, L., Isidor, B., Le Caignec, C., David, A., Obersztyn, E., Wisniowiecka-Kowalnik, B., Fox, M., Deignan, J. L., Vilain, E., Hendricks, E., Harr, M. H., Noon, S. E., Jackson, J. R., Wilkens, A., Mirzaa, G., Salamon, N., Abramson, J., Zackai, E. H., Krantz, I., Innes, A. M., Nelson, S. F., Grody, W. W., Quintero-Rivera, F. 2015; 23 (11): 1473-1481

    Abstract

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.European Journal of Human Genetics advance online publication, 6 May 2015; doi:10.1038/ejhg.2015.71.

    View details for DOI 10.1038/ejhg.2015.71

    View details for Web of Science ID 000362916200010

    View details for PubMedID 25944381

  • State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. Genes & development Yucel, G., Altindag, B., Gomez-Ospina, N., Rana, A., Panagiotakos, G., Lara, M. F., Dolmetsch, R., Oro, A. E. 2013; 27 (11): 1217-1222

    Abstract

    The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2(TS) acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.

    View details for DOI 10.1101/gad.216556.113

    View details for PubMedID 23752588

    View details for PubMedCentralID PMC3690395

  • A Promoter in the Coding Region of the Calcium Channel Gene CACNA1C Generates the Transcription Factor CCAT PLOS ONE Gomez-Ospina, N., Panagiotakos, G., Portmann, T., Pasca, S. P., Rabah, D., Budzillo, A., Kinet, J. P., Dolmetsch, R. E. 2013; 8 (4)

    Abstract

    The C-terminus of the voltage-gated calcium channel Cav1.2 encodes a transcription factor, the calcium channel associated transcriptional regulator (CCAT), that regulates neurite extension and inhibits Cav1.2 expression. The mechanisms by which CCAT is generated in neurons and myocytes are poorly understood. Here we show that CCAT is produced by activation of a cryptic promoter in exon 46 of CACNA1C, the gene that encodes CaV1.2. Expression of CCAT is independent of Cav1.2 expression in neuroblastoma cells, in mice, and in human neurons derived from induced pluripotent stem cells (iPSCs), providing strong evidence that CCAT is not generated by cleavage of CaV1.2. Analysis of the transcriptional start sites in CACNA1C and immune-blotting for channel proteins indicate that multiple proteins are generated from the 3' end of the CACNA1C gene. This study provides new insights into the regulation of CACNA1C, and provides an example of how exonic promoters contribute to the complexity of mammalian genomes.

    View details for DOI 10.1371/journal.pone.0060526

    View details for Web of Science ID 000317893400012

    View details for PubMedID 23613729

    View details for PubMedCentralID PMC3628902

  • Translocation Affecting Sonic Hedgehog Genes in Basal-Cell Carcinoma NEW ENGLAND JOURNAL OF MEDICINE Gomez-Ospina, N., Chang, A. L., Qu, K., Oro, A. E. 2012; 366 (23): 2233-2234

    View details for Web of Science ID 000304863400029

    View details for PubMedID 22670922

    View details for PubMedCentralID PMC3839666

  • The C terminus of the L-type voltage-gated calcium channel Ca(v)1.2 encodes a transcription factor CELL Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L., Dolmetsch, R. 2006; 127 (3): 591-606

    Abstract

    Voltage-gated calcium channels play a central role in regulating the electrical and biochemical properties of neurons and muscle cells. One of the ways in which calcium channels regulate long-lasting neuronal properties is by activating signaling pathways that control gene expression, but the mechanisms that link calcium channels to the nucleus are not well understood. We report that a C-terminal fragment of Ca(V)1.2, an L-type voltage-gated calcium channel (LTC), translocates to the nucleus and regulates transcription. We show that this calcium channel associated transcription regulator (CCAT) binds to a nuclear protein, associates with an endogenous promoter, and regulates the expression of a wide variety of endogenous genes important for neuronal signaling and excitability. The nuclear localization of CCAT is regulated both developmentally and by changes in intracellular calcium. These findings provide evidence that voltage-gated calcium channels can directly activate transcription and suggest a mechanism linking voltage-gated channels to the function and differentiation of excitable cells.

    View details for DOI 10.1016/j.cell.2006.10.017

    View details for Web of Science ID 000241937000022

    View details for PubMedID 17081980

  • Mutations in alpha-tubulin promote basal body maturation and flagellar assembly in the absence of delta-tubulin JOURNAL OF CELL SCIENCE Fromherz, S., Giddings, T. H., Gomez-Ospina, N., Dutcher, S. K. 2004; 117 (2): 303-314

    Abstract

    We have isolated suppressors of the deletion allele of delta-tubulin, uni3-1, in the biflagellate green alga Chlamydomonas reinhardtii. The deletion of delta-tubulin produces cells that assemble zero, one or two flagella and have basal bodies composed primarily of doublet rather than triplet microtubules. Flagellar number is completely restored in the suppressed strains. Most of the uni3-1 suppressors map to the TUA2 locus, which encodes alpha2-tubulin. Twelve independent tua2 mutations were sequenced. Amino acids D205 or A208, which are nearly invariant residues in alpha-tubulin, were altered. The tua2 mutations on their own have a second phenotype - they make the cells colchicine supersensitive. Colchicine supersensitivity itself is not needed for suppression and colchicine cannot phenocopy the suppression. The suppressors partially restore the assembly of triplet microtubules. These results suggest that the delta-tubulin plays two roles: it is needed for extension or stability of the triplet microtubule and also for early maturation of basal bodies. We suggest that the mutant alpha-tubulin promotes the early maturation of the basal body in the absence of delta-tubulin, perhaps through interactions with other partners, and this allows assembly of the flagella.

    View details for DOI 10.1242/jcs.00859

    View details for Web of Science ID 000188665400017

    View details for PubMedID 14676280

  • Tomographic evidence for continuous turnover of Golgi cisternae in Pichia pastoris MOLECULAR BIOLOGY OF THE CELL Mogelsvang, S., Gomez-Ospina, N., Soderholm, J., Glick, B. S., Staehelin, L. A. 2003; 14 (6): 2277-2291

    Abstract

    The budding yeast Pichia pastoris contains ordered Golgi stacks next to discrete transitional endoplasmic reticulum (tER) sites, making this organism ideal for structure-function studies of the secretory pathway. Here, we have used P. pastoris to test various models for Golgi trafficking. The experimental approach was to analyze P. pastoris tER-Golgi units by using cryofixed and freeze-substituted cells for electron microscope tomography, immunoelectron microscopy, and serial thin section analysis of entire cells. We find that tER sites and the adjacent Golgi stacks are enclosed in a ribosome-excluding "matrix." Each stack contains three to four cisternae, which can be classified as cis, medial, trans, or trans-Golgi network (TGN). No membrane continuities between compartments were detected. This work provides three major new insights. First, two types of transport vesicles accumulate at the tER-Golgi interface. Morphological analysis indicates that the center of the tER-Golgi interface contains COPII vesicles, whereas the periphery contains COPI vesicles. Second, fenestrae are absent from cis cisternae, but are present in medial through TGN cisternae. The number and distribution of the fenestrae suggest that they form at the edges of the medial cisternae and then migrate inward. Third, intact TGN cisternae apparently peel off from the Golgi stacks and persist for some time in the cytosol, and these "free-floating" TGN cisternae produce clathrin-coated vesicles. These observations are most readily explained by assuming that Golgi cisternae form at the cis face of the stack, progressively mature, and ultimately dissociate from the trans face of the stack.

    View details for Web of Science ID 000183524100009

    View details for PubMedID 12808029

  • Selective trafficking of non-cell-autonomous proteins mediated by NtNCAPP1 SCIENCE Lee, J. Y., Yoo, B. C., Rojas, M. R., Gomez-Ospina, N., Staehelin, L. A., Lucas, W. J. 2003; 299 (5605): 392-396

    Abstract

    In plants, cell-to-cell communication is mediated by plasmodesmata and involves the trafficking of non-cell-autonomous proteins (NCAPs). A component in this pathway, Nicotiana tabacum NON-CELL-AUTONOMOUS PATHWAY PROTEIN1 (NtNCAPP1), was affinity purified and cloned. Protein overlay assays and in vivo studies showed that NtNCAPP1 is located on the endoplasmic reticulum at the cell periphery and displays specificity in its interaction with NCAPs. Deletion of the NtNCAPP1 amino-terminal transmembrane domain produced a dominant-negative mutant that blocked the trafficking of specific NCAPs. Transgenic tobacco plants expressing this mutant form of NtNCAPP1 and plants in which the NtNCAPP1 gene was silenced were compromised in their ability to regulate leaf and floral development. These results support a model in which NCAP delivery to plasmodesmata is both selective and regulated.

    View details for Web of Science ID 000180426800045

    View details for PubMedID 12532017

  • The spindle checkpoint of Saccharomyces cerevisiae responds to separable microtubule-dependent events CURRENT BIOLOGY Daum, J. R., Gomez-Ospina, N., Winey, M., Burke, D. J. 2000; 10 (21): 1375-1378

    Abstract

    The spindle checkpoint regulates microtubule-based chromosome segregation and helps to maintain genomic stability [1,2]. Mutational inactivation of spindle checkpoint genes has been implicated in the progression of several types of human cancer. Recent evidence from budding yeast suggests that the spindle checkpoint is complex. Order-of-function experiments have defined two separable pathways within the checkpoint. One pathway, defined by MAD2, controls the metaphase-to-anaphase transition and the other, defined by BUB2, controls the exit from mitosis [3-6]. The relationships between the separate branches of the checkpoint, and especially the events that trigger the pathways, have not been defined. We localized a Bub2p-GFP fusion protein to the cytoplasmic side of the spindle pole body and used a kar9 mutant to show that cells with misoriented spindles are arrested in anaphase of mitosis. We used a kar9 bub2 double mutant to show that the arrest is BUB2 dependent. We conclude that the separate pathways of the spindle checkpoint respond to different classes of microtubules. The MAD2 branch of the pathway responds to kinetochore microtubule interactions and the BUB2 branch of the pathway operates within the cytoplasm, responding to spindle misorientation.

    View details for Web of Science ID 000165230100020

    View details for PubMedID 11084338

  • Yeast nuclear pore complex assembly defects determined by nuclear envelope reconstruction JOURNAL OF STRUCTURAL BIOLOGY Gomez-Ospina, N., Morgan, G., Giddings, T. H., Kosova, B., Hurt, E., Winey, M. 2000; 132 (1): 1-5

    Abstract

    Assembly of nuclear pore complexes (NPCs) is a critical yet poorly understood cellular function. One approach to studying NPC assembly is to identify yeast mutants defective in this process. This requires robust assays for NPC assembly that can be used for phenotypic analysis. We have previously reconstructed yeast nuclei from electron micrographs of serially sectioned cells to precisely determine the number of NPCs (Winey et al., 1997). Here we report the analysis of strains mutant in either of two nucleoporin-encoding genes, NIC96 (Zabel et al., 1996) and NUP192 (Kosova et al., 1999). Using conditional alleles of either gene, we have found that the NPC number falls significantly following shift to the restrictive temperature. We conclude that the drop in NPC number results from the failure to assemble new NPCs during cell divisions, leading to the dilution of NPCs that existed when the cells were shifted to the restrictive temperature. We are also able to document a subtle defect in NPC numbers in nup192-15 cells at their permissive temperature. The data presented here quantitatively demonstrate that NPC numbers fall in nic96-1 and nup192-15 strains upon shifting to the restrictive temperature, indicating that these gene products are required for NPC assembly.

    View details for Web of Science ID 000166379300001

    View details for PubMedID 11121302