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Current Research and Scholarly Interests

Hearing is one of the most sensitive functions controlled by thyroid hormone (TH). TH is required for the timely coordination of a complex set of differentiation events in the maturing cochlea. Hypothyroidism retards the differentiation of the cochlea, including synaptogenesis, neurogenesis and myelinogenesis. The mechanisms that prompt the progression of these developmental events are poorly understood. Our preliminary data shows that many genes are differentially regulated by thyroid hormone in the cochlea.
Identifying which of these genes play important roles in cochlear hair cell innervation and synapse formation will further basic understanding about how the auditory system develops. In addition, knowledge of these genes could help devise strategies for stimulating the innervation of newly generated hair cells. To establish or restore hearing, it is vital that newly formed hair cells be connected functionally to the brain. We expect that our research will contribute to this important clinical/translational research effort by identifying genes involved in stimulating innervation and synapse formation.


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    Afferent connections to the sensory inner (IHCs) and outer hair cells (OHCs) in the cochlea refine and functionally mature during the thyroid hormone (TH)-critical period of inner ear development that occurs perinatally in rodents. In this study, we investigated the effects of hypothyroidism on afferent type II innervation to outer hair cells using the Snell dwarf mouse (Pit1(dw)). Using a transgenic approach to specifically label type II spiral ganglion neurons (SGNs), we found that lack of TH causes persistence of excess type II SGN connections to the OHCs, as well as continued expression of the hair cell functional marker, otoferlin (OTOF), in the OHCs beyond the maturation period. We also observed a concurrent delay in efferent attachment to the OHCs. Supplementing with TH during the early postnatal period from postnatal day (P) 3 to P4 reversed the defect in type II SGN pruning but did not alter OTOF expression. Our results show that hypothyroidism causes a defect in the large-scale pruning of afferent type II SGNs in the cochlea, and a delay in efferent attachment and the maturation of OTOF expression. Our data suggest that the state of maturation of hair cells, as determined by OTOF expression, may not regulate the pruning of their afferent innervation.

    View details for DOI 10.1016/j.neuroscience.2015.11.020

    View details for Web of Science ID 000366855700016

    View details for PubMedID 26592716

  • Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses EUROPEAN JOURNAL OF NEUROSCIENCE Sundaresan, S., Kong, J., Fang, Q., Salles, F. T., Wangsawihardja, F., Ricci, A. J., Mustapha, M. 2016; 43 (2): 148-161


    Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1(dw) ) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1(dw) mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1(dw) IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1(dw) IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1(dw) IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses.

    View details for DOI 10.1111/ejn.13081

    View details for Web of Science ID 000368245600003

  • Increased sensitivity to kindling in mice lacking TSP1. Neuroscience Mendus, D., Rankin-Gee, E. K., Mustapha, M., Porter, B. E. 2015; 305: 302-308


    The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal α2δ subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and α2δ-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and α2δ-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility.

    View details for DOI 10.1016/j.neuroscience.2015.07.075

    View details for PubMedID 26241338

  • The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing. eLife Fang, Q., Indzhykulian, A. A., Mustapha, M., Riordan, G. P., Dolan, D. F., Friedman, T. B., Belyantseva, I. A., Frolenkov, G. I., Camper, S. A., Bird, J. E. 2015; 4


    The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture.

    View details for DOI 10.7554/eLife.08627

    View details for PubMedID 26302205

  • Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear EUROPEAN JOURNAL OF NEUROSCIENCE Mendus, D., Sundaresan, S., Grillet, N., Wangsawihardja, F., Leu, R., Mueller, U., Jones, S. M., Mustapha, M. 2014; 39 (8): 1256-1267


    Thrombospondins (TSPs) constitute a family of secreted extracellular matrix proteins that have been shown to be involved in the formation of synapses in the central nervous system. In this study, we show that TSP1 and TSP2 are expressed in the cochlea, and offer the first description of their putative roles in afferent synapse development and function in the inner ear. We examined mice with deletions of TSP1, TSP2 and both (TSP1/TSP2) for inner ear development and function. Immunostaining for synaptic markers indicated a significant decrease in the number of formed afferent synapses in the cochleae of TSP2 and TSP1/TSP2 knockout (KO) mice at postnatal day (P)29. In functional studies, TSP2 and TSP1/TSP2 KO mice showed elevated auditory brainstem response (ABR) thresholds as compared with wild-type littermates, starting at P15, with the most severe phenotype being seen for TSP1/TSP2 KO mice. TSP1/TSP2 KO mice also showed reduced wave I amplitudes of ABRs and vestibular evoked potentials, suggesting synaptic dysfunction in both the auditory and vestibular systems. Whereas ABR thresholds in TSP1 KO mice were relatively unaffected at early ages, TSP1/TSP2 KO mice showed the most severe phenotype among all of the genotypes tested, suggesting functional redundancy between the two genes. On the basis of the above results, we propose that TSPs play an important role in afferent synapse development and function of the inner ear.

    View details for DOI 10.1111/ejn.12486

    View details for Web of Science ID 000334506400002

    View details for PubMedID 24460873

  • A lack of immune system genes causes loss in high frequency hearing but does not disrupt cochlear synapse maturation in mice. PloS one Calton, M. A., Lee, D., Sundaresan, S., Mendus, D., Leu, R., Wangsawihardja, F., Johnson, K. R., Mustapha, M. 2014; 9 (5)


    Early cochlear development is marked by an exuberant outgrowth of neurites that innervate multiple targets. The establishment of mature cochlear neural circuits is, however, dependent on the pruning of inappropriate axons and synaptic connections. Such refinement also occurs in the central nervous system (CNS), and recently, genes ordinarily associated with immune and inflammatory processes have been shown to play roles in synaptic pruning in the brain. These molecules include the major histocompatibility complex class I (MHCI) genes, H2-Kb and H2-Db, and the complement cascade gene, C1qa. Since the mechanisms involved in synaptic refinement in the cochlea are not well understood, we investigated whether these immune system genes may be involved in this process and whether they are required for normal hearing function. Here we report that these genes are not necessary for normal synapse formation and refinement in the mouse cochlea. We further demonstrate that C1qa expression is not necessary for normal hearing in mice but the lack of expression of H2-Kb and H2-Db causes hearing impairment. These data underscore the importance of the highly polymorphic family of MHCI genes in hearing in mice and also suggest that factors and mechanisms regulating synaptic refinement in the cochlea may be distinct from those in the CNS.

    View details for DOI 10.1371/journal.pone.0094549

    View details for PubMedID 24804771

  • Genetic Background of Prop1(df) Mutants Provides Remarkable Protection Against Hypothyroidism-Induced Hearing Impairment JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY Fang, Q., Giordimaina, A. M., Dolan, D. F., Camper, S. A., Mustapha, M. 2012; 13 (2): 173-184


    Hypothyroidism is a cause of genetic and environmentally induced deafness. The sensitivity of cochlear development and function to thyroid hormone (TH) mandates understanding TH action in this sensory organ. Prop1(df) and Pou1f1(dw) mutant mice carry mutations in different pituitary transcription factors, each resulting in pituitary thyrotropin deficiency. Despite the same lack of detectable serum TH, these mutants have very different hearing abilities: Prop1(df) mutants are mildly affected, while Pou1f1(dw) mutants are completely deaf. Genetic studies show that this difference is attributable to the genetic backgrounds. Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects. We analyzed Prop1(df) mutants to identify processes in cochlear development that are disrupted in other hypothyroid animal models but protected in Prop1(df) mutants by the genetic background. The development of outer hair cell (OHC) function is delayed, but Prestin and KCNQ4 immunostaining appear normal in mature Prop1(df) mutants. The endocochlear potential and KCNJ10 immunostaining in the stria vascularis are indistinguishable from wild type, and no differences in neurofilament or synaptophysin staining are evident in Prop1(df) mutants. The synaptic vesicle protein otoferlin normally shifts expression from OHC to IHC as temporary afferent fibers beneath the OHC regress postnatally. Prop1(df) mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function. Thus, the genetic background of Prop1(df) mutants is remarkably protective for most functions affected in other hypothyroid mice. The Prop1(df) mutant is an attractive model for identifying the genes that protect against deafness.

    View details for DOI 10.1007/s10162-011-0302-3

    View details for Web of Science ID 000303893200002

    View details for PubMedID 22143287

  • High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects GENETIC TESTING AND MOLECULAR BIOMARKERS Ben Said, M., Hmani-Aifa, M., Amar, I., Baig, S. M., Mustapha, M., Delmaghani, S., Tlili, A., Ghorbel, A., Ayadi, H., Van Camp, G., Smith, R. J., Tekin, M., Masmoudi, S. 2010; 14 (3): 307-311


    Founder mutations, particularly 35delG in the GJB2 gene, have to a large extent contributed to the high frequency of autosomal recessive nonsyndromic hearing loss (ARNSHL). Mutations in transmembrane channel-like gene 1 (TMC1) cause ARNSHL. The p.R34X mutation is the most frequent known mutation in the TMC1 gene. To study the origin of this mutation and determine whether it arose in a common ancestor, we analyzed 21 polymorphic markers spanning the TMC1 gene in 11 unrelated individuals from Algeria, Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey who carry this mutation. In nine individuals, we observed significant linkage disequilibrium between p.R34X and five polymorphic markers within a 220 kb interval, suggesting that p.R34X arose from a common founder. We estimated the age of this mutation to be between 1075 and 1900 years, perhaps spreading along the third Hadramaout population movements during the seventh century. A second founder effect was observed in Turkish and Lebanese individuals with markers in a 920 kb interval. Screening for the TMC1 p.R34X mutation is indicated in the genetic evaluation of persons with ARNSHL from North African and Southwest Asia.

    View details for DOI 10.1089/gtmb.2009.0174

    View details for Web of Science ID 000279170100006

    View details for PubMedID 20373850

  • Deafness and Permanently Reduced Potassium Channel Gene Expression and Function in Hypothyroid Pit1(dw) Mutants JOURNAL OF NEUROSCIENCE Mustapha, M., Fang, Q., Gong, T., Dolan, D. F., Raphael, Y., Camper, S. A., Duncan, R. K. 2009; 29 (4): 1212-1223


    The absence of thyroid hormone (TH) during late gestation and early infancy can cause irreparable deafness in both humans and rodents. A variety of rodent models have been used in an effort to identify the underlying molecular mechanism. Here, we characterize a mouse model of secondary hypothyroidism, pituitary transcription factor 1 (Pit1(dw)), which has profound, congenital deafness that is rescued by oral TH replacement. These mutants have tectorial membrane abnormalities, including a prominent Hensen's stripe, elevated beta-tectorin composition, and disrupted striated-sheet matrix. They lack distortion product otoacoustic emissions and cochlear microphonic responses, and exhibit reduced endocochlear potentials, suggesting defects in outer hair cell function and potassium recycling. Auditory system and hair cell physiology, histology, and anatomy studies reveal novel defects of hormone deficiency related to deafness: (1) permanently impaired expression of KCNJ10 in the stria vascularis of Pit1(dw) mice, which likely contributes to the reduced endocochlear potential, (2) significant outer hair cell loss in the mutants, which may result from cellular stress induced by the lower KCNQ4 expression and current levels in Pit1(dw) mutant outer hair cells, and (3) sensory and strial cell deterioration, which may have implications for thyroid hormone dysregulation in age-related hearing impairment. In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1(dw) mice.

    View details for DOI 10.1523/JNEUROSCI.4957-08.2009

    View details for Web of Science ID 000262859000032

    View details for PubMedID 19176829

  • Whirler mutant hair cells have less severe pathology than shaker or double mutants JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY Mustapha, M., Beyer, L. A., Izumikawa, M., Swiderski, D. L., Dolan, D. F., Raphael, Y., Camper, S. A. 2007; 8 (3): 329-337


    MYOSIN XV is a motor protein that interacts with the PDZ domain-containing protein WHIRLIN and transports WHIRLIN to the tips of the stereocilia. Shaker 2 (sh2) mice have a mutation in the motor domain of MYOSIN XV and exhibit congenital deafness and circling behavior, probably because of abnormally short stereocilia. Whirler (wi) mice have a similar phenotype caused by a deletion in the third PDZ domain of WHIRLIN. We compared the morphology of Whrn (wi/wi) and Myo15 (sh2/sh2) sensory hair cells and found that Myo15 (sh2/sh2) have more frequent pathology at the base of inner hair cells than Whrn (wi/wi), and shorter outer hair cell stereocilia. Considering the functional and morphologic similarities in the phenotypes caused by mutations in Myo15 and Whrn, and the physical interaction between their encoded proteins, we used a genetic approach to test for functional overlap. Double heterozygotes (Myo15 (sh2/+), Whrn (wi/+)) have normal hearing and no increase in hearing loss compared to normal littermates. Single and double mutants (Myo15 (sh2/sh2), Whrn (wi/wi)) exhibit abnormal persistence of kinocilia and microvilli, and develop abnormal cytoskeletal architecture. Double mutants are also similar to the single mutants in viability, circling behavior, and lack of a Preyer reflex. The morphology of cochlear hair cell stereocilia in double mutants reflects a dominance of the more severe Myo15 (sh2/sh2) phenotype over the Whrn (wi/wi) phenotype. This suggests that MYOSIN XV may interact with other proteins besides WHIRLIN that are important for hair cell maturation.

    View details for DOI 10.1007/s10162-007-0083-x

    View details for Web of Science ID 000249395300002

    View details for PubMedID 17619105

  • Complexity and integration in the control of inner-ear development. Genome biology Swiderski, D. L., Gong, T., Mustapha, M. 2007; 8 (9): 315-?

    View details for PubMedID 17915040

  • Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31 NATURE GENETICS Mburu, P., Mustapha, M., Varela, A., Weil, D., El-Amraoui, A., Holme, R. H., Rump, A., Hardisty, R. E., Blanchard, S., Coimbra, R. S., Perfettini, I., Parkinson, N., Mallon, A. M., Glenister, P., Rogers, M. J., Paige, A. J., Moir, L., Clay, J., Rosenthal, A., Liu, X. Z., Blanco, G., STEEL, K. P., Petit, C., Brown, S. D. 2003; 34 (4): 421-428


    The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia.

    View details for DOI 10.1038/ng1208

    View details for Web of Science ID 000184470500020

    View details for PubMedID 12833159

  • Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin HUMAN MOLECULAR GENETICS Weil, D., El-Amraoui, A., Masmoudi, S., Mustapha, M., Kikkawa, Y., LAINE, S., Delmaghani, S., Adato, A., Nadifi, S., Zina, Z. B., Hamel, C., Gal, A., Ayadi, H., Yonekawa, H., Petit, C. 2003; 12 (5): 463-471


    Usher syndrome type I (USH1) is the most frequent cause of hereditary deaf-blindness in humans. Seven genetic loci (USH1A-G) have been implicated in this disease to date, and four of the corresponding genes have been identified: USH1B, C, D and F. We carried out fine mapping of USH1G (chromosome 17q24-25), restricting the location of this gene to an interval of 2.6 Mb and then screened genes present within this interval for mutations. The genes screened included the orthologue of the Sans gene, which is defective in the Jackson shaker deaf mutant and maps to the syntenic region in mice. In two consanguineous USH1G-affected families, we detected two different frameshift mutations in the SANS gene. Two brothers from a German family affected with USH1G were found to be compound heterozygotes for a frameshift and a missense mutation. These results demonstrate that SANS underlies USH1G. The SANS protein contains three ankyrin domains and a sterile alpha motif, and its C-terminal tripeptide presents a class I PDZ-binding motif. We showed, by means of co-transfection experiments, that SANS associates with harmonin, a PDZ domain-containing protein responsible for USH1C. In Jackson shaker mice the hair bundles, the mechanoreceptive structures of inner ear sensory cells, are disorganized. Based on the known interaction between USH1B (myosin VIIa), USH1C (harmonin) and USH1D (cadherin 23) proteins and the results obtained in this study, we suggest that a functional network formed by the USH1B, C, D and G proteins is responsible for the correct cohesion of the hair bundle.

    View details for DOI 10.1093/hmg/ddg051

    View details for Web of Science ID 000181379600002

    View details for PubMedID 12588794

  • Non-syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34.3 and prevalence of DFNB1 mutations EUROPEAN JOURNAL OF HUMAN GENETICS Medlej-Hashim, M., Mustapha, M., Chouery, E., Weil, D., Parronaud, J., Salem, N., Delague, V., Loiselet, J., Lathrop, M., Petit, C., Megarbane, A. 2002; 10 (6): 391-394


    Non-syndromic recessive deafness (NSRD) is the most commonly encountered form of hereditary hearing loss. The majority of NSRD cases in the Mediterranean area are linked to the DFNB1 locus (the connexin 26 GJB2 gene). Unrelated NSRD patients issued from 68 Jordanian families, were tested for mutations of the GJB2 gene by sequencing. Sixteen per cent of the families tested were linked to the DFNB1 locus. The 35delG was the only GJB2 mutation detected in these families. One of these families, presenting with four affected members and not linked to the gene, was subjected to a genome-wide search and was found to be mapped to 9q34.3 with a multipoint lodscore of 3.9. One candidate gene in the interval, coding for the chloride intracellular channel 3, CLIC3, was tested and excluded. The identification of a new NSRD locus, DFNB33, in one Jordanian family, shows the wide genetic heterogeneity that characterizes hearing impairment and the genetic diversity in Middle-Eastern populations.

    View details for DOI 10.1038/sj.ejhg.5200813

    View details for Web of Science ID 000176842600008

    View details for PubMedID 12080392

  • Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zwaenepoel, I., Mustapha, M., Leibovici, M., Verpy, E., Goodyear, R., Liu, X. Z., Nouaille, S., Nance, W. E., Kanaan, M., Avraham, K. B., Tekaia, F., Loiselet, J., Lathrop, M., Richardson, G., Petit, C. 2002; 99 (9): 6240-6245


    A 3,673-bp murine cDNA predicted to encode a glycosylphosphatidylinositol-anchored protein of 1,088 amino acids was isolated during a study aimed at identifying transcripts specifically expressed in the inner ear. This inner ear-specific protein, otoancorin, shares weak homology with megakaryocyte potentiating factor/mesothelin precursor. Otoancorin is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. In the cochlea, otoancorin is detected at two attachment zones of the tectorial membrane, a permanent one along the top of the spiral limbus and a transient one on the surface of the developing greater epithelial ridge. In the vestibule, otoancorin is present on the apical surface of nonsensory cells, where they contact the otoconial membranes and cupulae. The identification of the mutation (IVS12+2T>C) in the corresponding gene OTOA in one consanguineous Palestinian family affected by nonsyndromic recessive deafness DFNB22 assigns an essential function to otoancorin. We propose that otoancorin ensures the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells.

    View details for DOI 10.1073/pnas.082515999

    View details for Web of Science ID 000175377800089

    View details for PubMedID 11972037

  • A novel locus for Usher syndrome type I, USH1G, maps to chromosome 17q24-25 HUMAN GENETICS Mustapha, M., Chouery, E., Torchard-Pagnez, D., Nouaille, S., Khrais, A., Sayegh, F. N., Megarbane, A., Loiselet, J., Lathrop, M., Petit, C., Weil, D. 2002; 110 (4): 348-350


    Usher syndrome (USH) is an autosomal recessive disorder associated with sensorineural hearing impairment and progressive visual loss attributable to retinitis pigmentosa. This syndrome is both clinically and genetically heterogeneous. Three clinical types have been described of which type I (USH1) is the most severe. Six USH1 loci have been identified. We report a Palestinian consanguineous family from Jordan with three affected children. In view of the combination of profound hearing loss, vestibular dysfunction, and retinitis pigmentosa in the patients, we classified the disease as USH1. Linkage analysis excluded the involvement of any of the known USH1 loci. A genome-wide screening allowed us to map this novel locus, USH1G, in a 23-cM interval on chromosome 17q24-25. The USH1G interval overlaps the intervals for two dominant forms of isolated hearing loss, namely DFNA20 and DFNA26. Since several examples have been reported of syndromic and isolated forms of deafness being allelic, USH1G, DFNA20, and DFNA26 might result from alterations of the same gene. Finally, a mouse mutant, jackson shaker ( js), with deafness and circling behavior has been mapped to the murine homologous region on chromosome 11.

    View details for DOI 10.1007/s00439-002-0690-x

    View details for Web of Science ID 000175479900008

    View details for PubMedID 11941484

  • DFNB31, a recessive form of sensorineural hearing loss, maps to chromosome 9q32-34 EUROPEAN JOURNAL OF HUMAN GENETICS Mustapha, M., Chouery, E., Chardenoux, S., Naboulsi, M., Paronnaud, J., Lemainque, A., Megarbane, A., Loiselet, J., Weil, D., Lathrop, M., Petit, C. 2002; 10 (3): 210-212


    We report the identification of a novel locus responsible for an autosomal recessive form of hearing loss (DFNB) segregating in a Palestinian consanguineous family from Jordan. The affected individuals suffer from profound prelingual sensorineural hearing impairment. A genetic linkage with polymorphic markers surrounding D9S1776 was detected, thereby identifying a novel deafness locus, DFNB31. This locus could be assigned to a 9q32-34 region of 15 cM between markers D9S289 and D9S1881. The whirler (wi) mouse mutant, characterised by deafness and circling behaviour, maps to the corresponding region on the murine chromosome 4, thus suggesting that DFNB31 and whirler may result from orthologous gene defects.

    View details for DOI 10.1038/sj/ejhg/5200780

    View details for Web of Science ID 000175283300009

    View details for PubMedID 11973626

  • DFNB21. Advances in oto-rhino-laryngology Denoyelle, F., Mustapha, M., Petit, C. 2002; 61: 153-155

    View details for PubMedID 12408078

  • Autosomal recessive non-syndromic hearing loss in the Lebanese population: prevalence of the 30delG mutation and report of two novel mutations in the connexin 26 (GJB2) gene. Journal of medical genetics Mustapha, M., Salem, N., Delague, V., Chouery, E., Ghassibeh, M., Rai, M., Loiselet, J., Petit, C., Mégarbané, A. 2001; 38 (10): E36-?

    View details for PubMedID 11584050

    View details for PubMedCentralID PMC1734738

  • Exclusion of chromosome 15q21.1 in autosomal-recessive Weill-Marchesani syndrome in an inbred Lebanese family CLINICAL GENETICS Megarbane, A., Mustapha, M., Bleik, J., Waked, N., Delague, V., Loiselet, J. 2000; 58 (6): 473-478


    We report an inbred family where 3 siblings had short stature, brachydactyly, limitation of joint movements, microspherophakia, luxated lenses, glaucoma, and heart malformations. Parents of the affected siblings were relatively short, but did not have any of the other features present in their siblings. Those clinical features are consistent with the Weill Marchesani syndrome (MIM 277600). Both autosomal-recessive and autosomal-dominant pedigrees have been reported, with a possible linkage to chromosome 15q21.1 in the latter. Linkage analysis at 15q21.1 in this Lebanese family allowed us to exclude the role of this region in the etiology of the syndrome. Speculations regarding the pathogenesis of the disorder are discussed.

    View details for Web of Science ID 000165944100008

    View details for PubMedID 11149617

  • A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness NATURE GENETICS Yasunaga, S., Grati, M., Cohen-Salmon, M., El-Amraoui, A., Mustapha, M., Salem, N., El-Zir, E., Loiselet, J., Petit, C. 1999; 21 (4): 363-369


    Using a candidate gene approach, we identified a novel human gene, OTOF, underlying an autosomal recessive, nonsyndromic prelingual deafness, DFNB9. The same nonsense mutation was detected in four unrelated affected families of Lebanese origin. OTOF is the second member of a mammalian gene family related to Caenorhabditis elegans fer-1. It encodes a predicted cytosolic protein (of 1,230 aa) with three C2 domains and a single carboxy-terminal transmembrane domain. The sequence homologies and predicted structure of otoferlin, the protein encoded by OTOF, suggest its involvement in vesicle membrane fusion. In the inner ear, the expression of the orthologous mouse gene, mainly in the sensory hair cells, indicates that such a role could apply to synaptic vesicles.

    View details for Web of Science ID 000079439700016

    View details for PubMedID 10192385

  • An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21 HUMAN MOLECULAR GENETICS Mustapha, M., Weil, D., Chardenoux, S., Elias, S., El-Zir, E., Beckmann, J. S., Loiselet, J., Petit, C. 1999; 8 (3): 409-412


    In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family comprising nine members presenting with a pre-lingual severe to profound sensorineural isolated form of deafness. Linkage analysis led to the characterization of a new locus, DFNB21, which was assigned to chromosome 11q23-25. Already mapped to this chromosomal region was TECTA. This gene encodes alpha-tectorin, a 2155 amino acid protein which is a component of the tectorial membrane. This gene recently has been shown to be responsible for a dominant form of deafness, DFNA8/12. Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a G to A transition in the donor splice site (GT) of intron 9, predicted to lead to a truncated protein of 971 amino acids. This establishes that alpha-tectorin mutations can be responsible for both dominant and recessive forms of deafness. Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect. The present results provide genetic evidence for alpha-tectorin forming homo- or heteromeric structures.

    View details for Web of Science ID 000079000100003

    View details for PubMedID 9949200

  • Identification of a locus on chromosome 7q31, DFNB14, responsible for prelingual sensorineural non-syndromic deafness EUROPEAN JOURNAL OF HUMAN GENETICS Mustapha, M., Salem, N., Weil, D., El-Zir, E., Loiselet, J., Petit, C. 1998; 6 (6): 548-551


    In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family affected with a prelingual profound sensorineural isolated form of deafness. Segregation analysis resulted in a linkage with locus D7S554 to locus D7S2459 on 7q31, with a maximum lod score of 6.3. The causative gene was mapped to a 15 cM interval extending from D7S527 to D7S3074 (on the telomeric side). The distal limit of this interval could be located between D7S496 and D7S3074 which are the closest polymorphic loci flanking the gene underlying Pendred syndrome (PDS) on the centromeric and on the telomeric sides, respectively. To eliminate PDS as a candidate gene, its 21 exons were sequenced. No mutation was detected. This study therefore reports the identification of a novel locus, DFNB14, on chromosome 7q31, in a position proximal to PDS.

    View details for Web of Science ID 000077962600004

    View details for PubMedID 9887371

  • The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region HUMAN GENETICS Saouda, M., Mansour, A., Moglabey, Y. B., El Zir, E., Mustapha, M., Chaib, H., Nehme, A., Megarbane, A., Loiselet, J., Petit, C., Slim, R. 1998; 103 (2): 193-198


    Usher syndrome (USH) is an autosomal-recessive disease characterized by neurosensory deafness and progressive retinitis pigmentosa. So far, three clinical types of Usher syndrome have been defined, and are caused by defects at more than eight loci. We report the linkage analysis of seven Lebanese families with Usher syndrome, two with type I (USH1) and five with type II (USH2). We demonstrate that one family is linked to the USH1C locus, a rare form of USH1 only reported in the French Acadian population. Linkage analysis of the five USH2 families with recently mapped loci allowed us to reduce the USH2A candidate region to a very small interval flanked by D1S2646/D1S2629 and D1S2827. Furthermore, haplotype comparison between the different families suggests a founder effect for the USH2A mutation among the different Lebanese ethnic groups, while a genetic heterogeneity is noted for Usher syndrome type I.

    View details for Web of Science ID 000076035600014

    View details for PubMedID 9760205

  • A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36 EUROPEAN JOURNAL OF HUMAN GENETICS Mustapha, M., Chardenoux, S., Nieder, A., Salem, N., Weissenbach, J., El-Zir, E., Loiselet, J., Petit, C. 1998; 6 (3): 245-250


    Deafness is the most frequent sensorineural defect in children. The vast majority of the prelingual forms of isolated deafness are highly genetically heterogeneous with an autosomal recessive mode of inheritance. Using linkage analysis, we have mapped the gene responsible for a severe progressive sensorineural hearing loss, DFNB13, segregating in a large consanguineous family living in an isolated region in northern Lebanon. A maximum lod score of 4.5 was detected for markers D7S661-D7S498. Recombination events and homozygosity mapping by descent define a 17 cM gene interval in the chromosome region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

    View details for Web of Science ID 000074551200008

    View details for PubMedID 9781028

  • Further refinement of Pendred syndrome locus by homozygosity analysis to a 0.8 cM interval flanked by D7S496 and D7S2425 JOURNAL OF MEDICAL GENETICS Mustapha, M., Azar, S. T., Moglabey, Y. B., Saouda, M., Zeitoun, G., Loiselet, J., Slim, R. 1998; 35 (3): 202-204


    Pendred syndrome is an autosomal recessive disease characterised by congenital sensorineural deafness and goitre. The gene responsible for Pendred syndrome has been mapped to chromosome 7q31 in a 5.5 centimorgan (cM) interval flanked by D7S501 and D7S523. This interval was recently refined a to 1.7 cM interval located between D7S501 and D7S692. In the present study, we report linkage analysis data on a large consanguineous family genotyped with eight microsatellite markers located between D7S501 and D7S523. Complete cosegregation with the disease locus was observed with the loci analysed, which further supports locus homogeneity for Pendred syndrome and close linkage to this region. Haplotype analysis placed the Pendred syndrome gene between D7S496 and D7S2425 in a 0.8 cM interval. This additional refinement of the Pendred syndrome region will facilitate the construction of a physical map of the region and will help the identification of candidate genes.

    View details for Web of Science ID 000072352900005

    View details for PubMedID 9541103

  • Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene HUMAN MOLECULAR GENETICS Denoyelle, F., Weil, D., Maw, M. A., Wilcox, S. A., Lench, N. J., ALLENPOWELL, D. R., Osborn, A. H., Dahl, H. H., Middleton, A., Houseman, M. J., Dode, C., Marlin, S., BoulilaElGgaied, A., Grati, M., Ayadi, H., BENARAB, S., Bitoun, P., LINAGRANADE, G., Godet, J., Mustapha, M., Loiselet, J., ElZir, E., Aubois, A., Joannard, A., Levilliers, J., Garabedian, E. N., Mueller, R. F., Gardner, R. J., Petit, C. 1997; 6 (12): 2173-2177


    Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.

    View details for Web of Science ID A1997YF21200022

    View details for PubMedID 9336442