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1.
Proc Natl Acad Sci U S A ; 113(30): 8508-13, 2016 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-27402757

RESUMEN

Efficient pluripotent stem cell guidance protocols for the production of human posterior cranial placodes such as the otic placode that gives rise to the inner ear do not exist. Here we use a systematic approach including defined monolayer culture, signaling modulation, and single-cell gene expression analysis to delineate a developmental trajectory for human otic lineage specification in vitro. We found that modulation of bone morphogenetic protein (BMP) and WNT signaling combined with FGF and retinoic acid treatments over the course of 18 days generates cell populations that develop chronological expression of marker genes of non-neural ectoderm, preplacodal ectoderm, and early otic lineage. Gene expression along this differentiation path is distinct from other lineages such as endoderm, mesendoderm, and neural ectoderm. Single-cell analysis exposed the heterogeneity of differentiating cells and allowed discrimination of non-neural ectoderm and otic lineage cells from off-target populations. Pseudotemporal ordering of human embryonic stem cell and induced pluripotent stem cell-derived single-cell gene expression profiles revealed an initially synchronous guidance toward non-neural ectoderm, followed by comparatively asynchronous occurrences of preplacodal and otic marker genes. Positive correlation of marker gene expression between both cell lines and resemblance to mouse embryonic day 10.5 otocyst cells implied reasonable robustness of the guidance protocol. Single-cell trajectory analysis further revealed that otic progenitor cell types are induced in monolayer cultures, but further development appears impeded, likely because of lack of a lineage-stabilizing microenvironment. Our results provide a framework for future exploration of stabilizing microenvironments for efficient differentiation of stem cell-generated human otic cell types.


Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Oído Interno/citología , Ectodermo/citología , Análisis de la Célula Individual/métodos , Animales , Proteínas Morfogenéticas Óseas/genética , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/genética , Células Cultivadas , Oído Interno/embriología , Ectodermo/efectos de los fármacos , Ectodermo/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/genética
2.
J Med Genet ; 52(8): 523-31, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25986071

RESUMEN

BACKGROUND: Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified. METHODS: We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family. RESULTS: We identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD. CONCLUSIONS: Variants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success.


Asunto(s)
Pérdida Auditiva Central/genética , Animales , Factor Inductor de la Apoptosis/química , Factor Inductor de la Apoptosis/genética , Mapeo Cromosómico , Estudios de Cohortes , Análisis Mutacional de ADN , Exoma/genética , Femenino , Genes Ligados a X , Pérdida Auditiva Central/patología , Humanos , Masculino , Ratones , Mutación Missense , Linaje , Estructura Terciaria de Proteína
3.
Am J Hum Genet ; 84(3): 328-38, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19230858

RESUMEN

Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Genoma Humano , Proteínas del Tejido Nervioso/genética , Otosclerosis/genética , Serina Endopeptidasas/genética , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/biosíntesis , Oído Interno/metabolismo , Proteínas de la Matriz Extracelular/biosíntesis , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Otosclerosis/metabolismo , Polimorfismo de Nucleótido Simple , Proteína Reelina , Serina Endopeptidasas/biosíntesis
4.
Am J Med Genet A ; 158A(5): 1066-70, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22489040

RESUMEN

Otosclerosis is a disease of abnormal bone remodeling in the human otic capsule that can lead to progressive hearing loss. Little of the underlying disease etiology has been elucidated thus far, although several studies have suggested that COL1A1 may play a role based on its importance in bone metabolism and other diseases like osteoporosis and osteogenesis imperfecta. Genetic association studies between COL1A1 and otosclerosis, however, have been contradictory. To resolve this issue, we studied a large Belgian-Dutch and a Swiss population for a genetic association between COL1A1 and otosclerosis and additionally performed a meta-analysis to investigate the overall genetic effect of COL1A1 on all otosclerosis populations studied to date. We found a significant association both in the Belgian-Dutch population and in the meta-analysis. In aggregate, our analysis supports evidence for an association between COL1A1 and otosclerosis although effect sizes of the variants reported in the initial studies are likely to be an overestimate of true effect sizes.


Asunto(s)
Colágeno Tipo I/genética , Estudios de Asociación Genética , Otosclerosis/genética , Bélgica , Cadena alfa 1 del Colágeno Tipo I , Humanos , Países Bajos , Otosclerosis/epidemiología
5.
Ann Hum Genet ; 74(5): 399-405, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20642811

RESUMEN

Otosclerosis is a common form of conductive hearing loss, caused by an abnormal bone remodelling in the otic capsule. Both environmental and genetic factors have been implicated in the etiology of this disease. A recent genome wide association study identified two regions associated with otosclerosis, one on chr7q22.1, located in the RELN gene, and one on chr11q13.1. A second study in four European populations has replicated the association of the RELN gene with otosclerosis. To investigate the association of these loci with otosclerosis in a non-European population, we tested 11 SNPs from the two regions in 149 unrelated Tunisian patients and 152 controls. Four SNPs were significantly associated with otosclerosis. Three SNPs are located in the RELN region and the last one is located in the region on chromosome 11. We also observed a significant interaction with gender for rs3914132. This suggests an influence of sex on the association of RELN with otosclerosis. A meta-analysis showed that the disease-associated alleles in the Tunisian sample are the same as in all previously reported associations. Our study provides additional evidence implicating RELN in the development of otosclerosis. Additional functional studies should determine the role of RELN in the physiopathology of this disease.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Otosclerosis/genética , Polimorfismo de Nucleótido Simple , Serina Endopeptidasas/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 3/genética , Femenino , Humanos , Masculino , Otosclerosis/fisiopatología , Proteína Reelina , Caracteres Sexuales , Túnez
6.
Hum Genet ; 127(2): 155-62, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19847460

RESUMEN

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian-Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Proteínas del Tejido Nervioso/genética , Otosclerosis/genética , Polimorfismo de Nucleótido Simple , Serina Endopeptidasas/genética , Femenino , Frecuencia de los Genes , Heterogeneidad Genética , Genotipo , Alemania , Pruebas Auditivas , Humanos , Italia , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Metaanálisis como Asunto , Otosclerosis/diagnóstico , Proteína Reelina , Rumanía , Suiza
7.
Hear Res ; 240(1-2): 80-6, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18430532

RESUMEN

Otosclerosis is a complex disease that results in a common form of conductive hearing loss due to impaired mobility of the stapes. Stapedial motion becomes compromised secondary to invasion of otosclerotic foci into the stapedio-vestibular joint. Although environmental factors and genetic causes have been implicated in this process, the pathogenesis of otosclerosis remains poorly understood. To identify molecular contributors to otosclerosis we completed a microarray study of otosclerotic stapedial footplates. Stapes footplate samples from otosclerosis and control patients were used in the analysis. One-hundred-and-ten genes were found to be differentially expressed in otosclerosis samples. Ontological analysis of differentially expressed genes in otosclerosis provides evidence for the involvement of a number of pathways in the disease process that include interleukin signaling, inflammation and signal transduction, suggesting that aberrant regulation of these pathways leads to abnormal bone remodeling. Functional analyses of genes from this study will enhance our understanding of the pathogenesis of this disease.


Asunto(s)
Remodelación Ósea/genética , Perfilación de la Expresión Génica , Osteosclerosis/genética , Estribo/fisiopatología , Perfilación de la Expresión Génica/métodos , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosclerosis/metabolismo , Osteosclerosis/fisiopatología , ARN/análisis , Estribo/química
8.
Nat Commun ; 9(1): 4027, 2018 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-30279445

RESUMEN

Sensory hair cells located in the organ of Corti are essential for cochlear mechanosensation. Their loss is irreversible in humans resulting in permanent hearing loss. The development of therapeutic interventions for hearing loss requires fundamental knowledge about similarities and potential differences between animal models and human development as well as the establishment of human cell based-assays. Here we analyze gene and protein expression of the developing human inner ear in a temporal window spanning from week 8 to 12 post conception, when cochlear hair cells become specified. Utilizing surface markers for the cochlear prosensory domain, namely EPCAM and CD271, we purify postmitotic hair cell progenitors that, when placed in culture in three-dimensional organoids, regain proliferative potential and eventually differentiate to hair cell-like cells in vitro. These results provide a foundation for comparative studies with otic cells generated from human pluripotent stem cells and for establishing novel platforms for drug validation.


Asunto(s)
Órgano Espiral/embriología , Diferenciación Celular , Separación Celular/métodos , Técnicas de Cocultivo , Molécula de Adhesión Celular Epitelial/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo , Órgano Espiral/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo
10.
Stem Cells Dev ; 23(11): 1275-84, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24512547

RESUMEN

In mammals, the permanence of many forms of hearing loss is the result of the inner ear's inability to replace lost sensory hair cells. Here, we apply a differentiation strategy to guide human embryonic stem cells (hESCs) into cells of the otic lineage using chemically defined attached-substrate conditions. The generation of human otic progenitor cells was dependent on fibroblast growth factor (FGF) signaling, and protracted culture led to the upregulation of markers indicative of differentiated inner ear sensory epithelia. Using a transgenic ESC reporter line based on a murine Atoh1 enhancer, we show that differentiated hair cell-like cells express multiple hair cell markers simultaneously. Hair cell-like cells displayed protrusions reminiscent of stereociliary bundles, but failed to fully mature into cells with typical hair cell cytoarchitecture. We conclude that optimized defined conditions can be used in vitro to attain otic progenitor specification and sensory cell differentiation.


Asunto(s)
Diferenciación Celular , Células Madre Embrionarias/fisiología , Células Ciliadas Auditivas Internas/fisiología , Biomarcadores/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular/genética , Células Cultivadas , Oído Interno/citología , Oído Interno/metabolismo , Células Madre Embrionarias/citología , Epitelio/metabolismo , Regulación de la Expresión Génica , Células Ciliadas Auditivas Internas/citología , Humanos
11.
Otol Neurotol ; 35(3): 395-400, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24492129

RESUMEN

HYPOTHESIS: Genetic variation in BMP2 and BMP4 found in otosclerosis patients result in altered Smad signaling. BACKGROUND: Otosclerosis is a common form of adult-onset conductive hearing loss resulting from abnormal bone remodeling of the bony labyrinth that surrounds the inner ear. Both genetic and environmental factors are implicated in the disease, yet very little is known about its pathogenesis. The evidence for a genetic component has been established through family-based linkage and population-based association studies. Previously, members of the TGF-ß superfamily of genes have been associated with otosclerosis. METHODS: Sequencing of BMP2 and BMP4 coding regions was performed to identify common and rare variation in German otosclerosis patients compared with controls. Functional analyses of rare variation in the patient cohort were conducted by exposing an osteosarcoma cell line to conditioned media containing either wild type or variant forms of BMP2 or BMP4 and analyzing Smad1/5/8 phosphorylation. RESULTS: Although no significant association with common variation in these 2 genes was detected, there were 8 singleton variants identified in the German population. Of the 4 coding variants found solely in otosclerosis patients, two--BMP4(N150K) and BMP2(K357-R396del)--were found to decrease Smad1/5/8 signaling. CONCLUSION: Rare variants in BMP2 and BMP4 are not a major genetic component in the otosclerosis population. However, those with functional affect showed decreased Smad signaling. Further analysis of Smad signaling molecules should be performed to determine if these pathways in combination are a major contributor to otosclerosis, which could lead to additional treatment options for otosclerosis patients.


Asunto(s)
Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 4/genética , Otosclerosis/genética , Transducción de Señal/genética , Proteínas Smad/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Femenino , Estudios de Asociación Genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Otosclerosis/metabolismo , Fosforilación , Polimorfismo de Nucleótido Simple , Adulto Joven
12.
Adv Otorhinolaryngol ; 70: 122-129, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21358194

RESUMEN

Otosclerosis is one of the more common forms of adult-onset hearing loss with a prevalence of 0.3-0.4% in Caucasians. It is typically characterized by a conductive hearing loss due to labyrinthine endochondral sclerosis that upon stapedio-vestibular joint invasion results in loss of free motion of the stapes. Its etiology remains poorly understood with both environmental factors and genetic causes implicated in its development. Several environmental influences have been studied and numerous genomic loci have been mapped in families segregating autosomal-dominant otosclerosis. Population-based studies have also identified associations with several genes. These advances are improving our understanding of this complex disease.


Asunto(s)
Otosclerosis/genética , Expresión Génica , Ligamiento Genético , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Otosclerosis/epidemiología , Otosclerosis/etiología , Prevalencia , Factores de Riesgo
13.
Laryngoscope ; 121(6): 1184-6, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21495045

RESUMEN

Several mitochondrial DNA variants increase risk for developing sensorineural hearing loss following exposure to aminoglycoside antibiotics, a particular concern in the premature infant population, as many of these babies spend time in neonatal intensive care units and are treated with aminoglycosides. To determine the relative prevalence of five mitochondrial DNA variants in the 12S rRNA gene, MT-RNR1, we genotyped 703 neonatal intensive care unit patients and 1473 individuals from the general Iowa population. We found that the aggregate frequency of these variants (∼1.8%) was comparable between populations. Although no hearing loss was detected by newborn hearing screens in the at-risk patients, these neonatal intensive care unit graduates have an increased life-time risk for developing aminoglycoside-induced deafness.


Asunto(s)
ADN Mitocondrial/genética , Predisposición Genética a la Enfermedad/genética , Pérdida Auditiva Sensorineural/genética , ARN Ribosómico/genética , Aminoglicósidos/efectos adversos , Femenino , Genotipo , Pérdida Auditiva Sensorineural/inducido químicamente , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Masculino , Mutación , Tamizaje Neonatal
14.
Hear Res ; 266(1-2): 70-4, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19607896

RESUMEN

Otosclerosis is a common form of conductive hearing loss with a prevalence of 0.3-0.4% in white adults. It is characterized by labyrinthine endochondral sclerosis which may invade the stapedio-vestibular joint and interfere with free motion of the stapes. Both environmental factors and genetic causes have been implicated in the disease process; however, the pathogenesis of otosclerosis still remains poorly understood. To date, several loci have been mapped in families segregating autosomal dominant otosclerosis although no disease-causing mutations have been identified. In contrast, several association studies have implicated specific genes but their effects on risk-of-disease are small. The goal of this paper is to review the genetics of otosclerosis and to provide insight into studies that could be performed to elucidate disease pathogenesis.


Asunto(s)
Ligamiento Genético , Otosclerosis/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Herencia , Humanos , Otosclerosis/patología , Otosclerosis/fisiopatología , Linaje , Fenotipo
15.
Otol Neurotol ; 30(8): 1079-83, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19503013

RESUMEN

HYPOTHESIS/BACKGROUND: Otosclerosis is a frequent cause of hearing impairment in the Caucasian population and is characterized by abnormal bone remodeling of the otic capsule. Associations with several genes have been reported, and recently, an association between the renin-angiotensin-aldosterone system and otosclerosis has been suggested. Polymorphisms in 3 genes were investigated: angiotensinogen (AGT), angiotensin I-converting enzyme (ACE), and angiotensin II receptor, type 1. The polymorphisms in AGT and ACE were associated with disease, and both were reported to interact with each other. In the current study, a replication study was done in a large Belgian-Dutch population to investigate whether this association could be replicated. METHODS: The same 3 polymorphisms in AGT, ACE, and angiotensin II receptor, type 1 as analyzed in the original study were investigated in 692 otosclerosis patients and 692 controls of Belgian-Dutch origin. RESULTS: None of the polymorphisms were significantly associated with disease. Interaction between AGT and ACE polymorphisms was not significant either. CONCLUSION: We could not confirm the association between AGT and ACE, nor could we find evidence for interaction between both genes in otosclerosis. Because the current patient set is much larger than the one from the original study, this study holds sufficient power to detect the previously reported associations. Nonreplication in this case probably indicates that the initial results were false positive, although a role for these genes in otosclerosis cannot be definitively ruled out.


Asunto(s)
Otosclerosis/epidemiología , Otosclerosis/genética , Sistema Renina-Angiotensina/genética , Angiotensinógeno/genética , Bélgica/epidemiología , ADN/genética , Interpretación Estadística de Datos , Genotipo , Países Bajos/epidemiología , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Receptor de Angiotensina Tipo 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
16.
J Bone Miner Res ; 23(4): 507-16, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18021008

RESUMEN

UNLABELLED: We studied the role of polymorphisms in 13 candidate genes on the risk of otosclerosis in two large independent case-control sets. We found significant association in both populations with BMP2 and BMP4, implicating these two genes in the pathogenesis of this disease. INTRODUCTION: Otosclerosis is a progressive disorder of the human temporal bone that leads to conductive hearing loss and in some cases sensorineural or mixed hearing loss. In a few families, it segregates as a monogenic disease with reduced penetrance, but in most patients, otosclerosis is more appropriately considered a complex disorder influenced by genetic and environmental factors. MATERIALS AND METHODS: To identify major genetic factors in otosclerosis, we used a candidate gene approach to study two large independent case-control sets of Belgian-Dutch and French origin. Tag single nucleotide polymorphisms (SNPs) in 13 candidate susceptibility genes were studied in a stepwise strategy. RESULTS: Two SNPs were identified that showed the same significant effect in both populations. The first SNP, rs3178250, is located in the 3' untranslated region of BMP2. Individuals homozygote for the C allele are protected against otosclerosis (combined populations: p = 2.2 x 10(-4); OR = 2.027; 95% CI = 1.380-2.979). The second SNP, rs17563, is an amino acid changing (p.Ala152Val) SNP located in BMP4. The G allele, coding for the amino acid alanine, confers susceptibility in both populations (combined populations: p = 0.002; OR = 1.209; 95% CI: 1.070-1.370). CONCLUSIONS: These results indicate that polymorphisms in the BMP2 and BMP4 genes, both members of the TGF-beta superfamily, contribute to the susceptibility to otosclerosis and further strengthen the results from the recently reported association of TGFB1 with this disease.


Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Otosclerosis/fisiopatología , Factor de Crecimiento Transformador beta/fisiología , Proteína Morfogenética Ósea 2 , Proteína Morfogenética Ósea 4 , Proteínas Morfogenéticas Óseas/genética , Estudios de Casos y Controles , Femenino , Pérdida Auditiva/genética , Humanos , Masculino , Otosclerosis/genética , Polimorfismo de Nucleótido Simple , Factor de Crecimiento Transformador beta/genética
17.
Hum Mol Genet ; 16(17): 2021-30, 2007 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-17588962

RESUMEN

Otosclerosis is a progressive hearing loss characterized by an abnormal bone homeostasis of the otic capsule that leads to stapes fixation. Although its etiology remains unknown, otosclerosis can be considered a complex disease. Transforming growth factor-beta 1 (TGF-beta1) was chosen for a case-control association study, because of several non-genetic indications of involvement in otosclerosis. Single nucleotide polymorphism (SNP) analysis in a large Belgian-Dutch sample set gave significant results (P = 0.0044) for an amino acid changing SNP, T263I. Analysis of an independent French population replicated this association with SNP T263I (P = 0.00019). The results remained significant after multiple testing correction in both populations. Haplotype analysis and the results of an independent effect test using the weighted haplotype (WHAP) computer program in both populations were both compatible with SNP T263I being the only causal variant. The variant I263 is under-represented in otosclerosis patients and hence protective against the disease. Combining the data of both case-control groups for SNP T263I with a Mantel-Haenszel estimate of common odds ratios gave a very significant result (P = 9.2 x 10(-6)). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-beta1 is more active than the WT variant T263 (P = 1.6 x 10(-6)). On the basis of very low P-values, replication in an independent population and a functional effect of the protective variant, we conclude that TGF-beta1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.


Asunto(s)
Otosclerosis/genética , Polimorfismo de Nucleótido Simple , Factor de Crecimiento Transformador beta1/genética , Sustitución de Aminoácidos , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Variación Genética , Genética de Población , Genotipo , Haplotipos , Humanos , Modelos Biológicos , Otosclerosis/etnología , Otosclerosis/etiología , Fenotipo , Análisis de Secuencia de ADN , Población Blanca
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