Molecular Analysis Of Human Hereditary Deafness
人类遗传性耳聋的分子分析
基本信息
- 批准号:7733880
- 负责人:
- 金额:$ 229.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdultAffectAgeAllelesAmericanAuditoryBelgiumBenignBilateralBirthCampingCandidate Disease GeneCell SurvivalCellsChildChronicCleft PalateClinicalComplexConserved SequenceCounselingCrista ampullarisCutaneousDataDefectDevelopmentDiabetes MellitusDiseaseDisruptionDizzinessDysplasiaEarEnvironmental Risk FactorEpidermodysplasia VerruciformisEquilibriumEtiologyFamilyFamily StudyGaitGene ProteinsGenesGeneticGenetic MarkersGenetic TranscriptionGenotypeGoalsGoiterHair CellsHaplogroupHaplotypesHearingHearing Impaired PersonsHereditary DiseaseHumanHuman PapillomavirusHyperphagiaIn SituIndividualInfectionInheritance PatternsInheritedInsulin ResistanceIodineKnock-in MouseKnock-outKnockout MiceLaboratory ResearchLabyrinthLacZ GenesLateralLinkLymphoid CellMeasuresMedical SurveillanceMicroarray AnalysisMitochondriaMolecularMolecular AnalysisMolecular DiagnosisMusMutateMutationNumbersObesityOrganOther GeneticsPakistanPapillomaPapillomavirus InfectionsPathogenicityPatientsPerchloratesPhenotypePredispositionProteinsRecurrenceReporterReporter GenesReportingRisk EstimateSamplingSemicircular canal structureSensorineural Hearing LossSensorySerine-Specific tRNASkinSkin CarcinomaStructureStructure of parenchyma of lungSurveysSyndromeSystemTemporal bone structureTestingThyroid GlandUniversitiesVariantVestibular AqueductWorkYeastsbasecohortcomparative genomic hybridizationdeafnesshearing impairmentinsightmalformationmitochondrial genomemutantnoveloutcome forecastresponsesegregationtraffickingyeast two hybrid system
项目摘要
1. We are studying the transmembrane channel-like (TMC) genes 1 and 2. We have generated mice segregating knockout (null) alleles of Tmc1 and Tmc2. We are characterizing their mutant auditory and vestibular (balance) phenotypes. Mice that are homozygous for knockout alleles of both genes are deaf and have abnormal vestibular function. Mice that are homozygous for the Tmc1 knockout allele are deaf. Mice that are homozygous for the Tmc2 knockout allele have normal hearing and balance. These results indicate that both Tmc1 and Tmc2 are required for normal vestibular function (balance), whereas only Tmc1 is required for hearing. We use LacZ reporter genes in the knockout mice to study where the genetic interaction might be taking place. The Tmc1 reporter is expressed in hair cells of all of the vestibular end organs whereas the Tmc2 reporter is expressed in hair cells of the cristae ampullaris. We are now using hair cell markers to determine if these genes are expressed in type 1 or type 2 hair cells, or both. We are collaborating with Dr. Charley Della Santina to measure vestibulo-ocular responses in the mice to determine if their abnormal balance and gait is due to abnormal function of the semicircular canals (cristae) or other parts of the vestibular system.
2. We used a yeast two-hybrid screen to isolate genes encoding proteins that potentially interact with TMC1. We narrowed the list to a few candidate genes implicated in vesicular trafficking and in antiapoptosis and cell survival. We are using a combination of approaches to determine which interactions occur in situ in hair cells.
3. We generated knockout mice for Tmc6 and Tmc8 to better understand the function(s) of Tmc genes and proteins. Mutations in human TMC6 or TMC8 genes cause epidermodysplasia verruciformis, a recessive disease resulting in chronic cutaneous HPV infections (papillomas) with increased susceptibility to non-melanoma skin cancers. We have done extensive RNA expression analyses to show that Tmc6 and Tmc8 are primarily expressed in lymphoid cells and tissues and lung and skin, and primarily during development. The homozygous knockout mice have no obvious phenotypic abnormalities, so we are collaborating with Dr. Paul Lambert to determine if these mice have alterations in their susceptibility or response to papillomavirus infection.
4. We are continuing our work to identify the gene mutated in the mouse Twirler strain. Heterozygous Twirler mice have inner ear malformations and obesity, whereas homozygous mice are born with cleft palate and die at birth. The critical interval containing the Twirler gene is approximately 750 kilobases and contains one known gene and two predicted genes. We have identified a probable mutation. We have generated a knock-in mouse line with this mutation to confirm its pathogenicity. We have completed a comprehensive characterization of the Twirler obesity and inner ear phenotypes. The obesity phenotype is associated with hyperphagia of unknown etiology and insulin-resistant diabetes mellitus. The inner ear phenotype is characterized by hypoplasia or dysplasia of the semicircular canals; the lateral canals are most severely affected.
5. Enlargement of the vestibular aqueduct (EVA) is the most commonly detected radiologic malformation in temporal bones of individuals with hearing loss. A significant proportion of EVA cases have been reported to be associated with mutations of the SLC26A4 gene, in which mutations cause Pendred syndrome. PS is an autosomal recessive disorder comprised of bilateral sensorineural hearing loss and a defect in the ability of the thyroid gland to organify iodine. EVA is a universal finding in the ears of affected PS individuals. PS is correlated with two mutant SLC26A4 alleles, and nonsyndromic EVA is associated with one or zero mutant SLC26A4 alleles. Based upon our data, we hypothesize that one or more other genetic or environmental factors may act alone or in combination with a single SLC26A4 mutation to cause EVA. We have completed a comparative genome hybridization-microarray analysis to search for deletion and duplication mutations of SLC26A4 that might cause EVA. We have also PCR-amplified and sequenced all noncoding conserved sequences in and around SLC26A4. We found not evidence for such mutations.
We have completed segregation analyses of EVA to gain insight into the causes of EVA in patients with one or zero mutant alleles. The results are consistent with inheritance of a second recessive allele in the patients with one detectable SLC26A4 mutation, whereas the results for patients with no mutant alleles of SLC26A4 suggest one or more of the following: autosomal recessive inheritance of alleles at another locus, non-genetic causes, a complex etiology of two or more genetic and/or non-genetic factors, or a variety of different etiologies among different patients. These results yield recurrence risk estimates, dependent upon the number of SLC26A4 mutant alleles, that are very helpful for counseling patients and families with EVA.
We analyzed our genotype and phenotype data to identify clinical features that guide molecular diagnosis or clinical prognosis. We comprehensively and quantitatively analyzed the thyroid phenotypes in our EVA cohort. Our study is the first to rigorously analyze and describe the ultrasonographic phenotype of the thyroid gland in EVA patients. Our results show that thyroid gland volume (goiter) is dependent upon the number of mutant alleles in pre-pubescent subjects whereas it is dependent upon age in post-pubescent subjects. Therefore goiter is a more specific sign of biallelic SlC264A4 mutations (Pendred syndrome) in children than in adults. We continue to observe a strong correlation of an abnormal perchlorate discharge test with two mutant alleles of SLC26A4. Our data provides a basis for the surveillance and management of the thyroid gland in EVA subjects.
We have completed functional studies of several missense substitutions of SLC26A4 that have always or usually been detected as the single SLC26A4 variant in nonsyndromic EVA patients and shown that they appear to have wild type trafficking and functional activity, indicating they are benign polymorphic variants. These results have important implications for molecular diagnosis of EVA patients, as well as for categorizing patients according to SLC26A4 genotype for studies to identify other causes of EVA.
6. We ascertained a large North American family segregating progressive, nonsyndromic sensorineural hearing loss in a matrilineal/maternal/mitochondrial pattern of inheritance. We sequenced the entire mitochondrial genome in several affected individuals and have identified a rare mutation in the tRNA-Ser(UCN) gene. We analyzed the mitochondrial haplogroup associated with this mutation and compared it to that associated with this same mutation in a previously reported family. Our results show the haplogroups are different, and we did not find the mutation in haplogroup-matched normal control samples. Our study confirms the pathogenicicty of the tRNA-Ser(UCN) mutation in sensorineural hearing loss.
7. The research laboratory of Dr. Guy Van Camp (University of Antwerp, Belgium) discovered a family with dominant progressive hearing loss caused by the D572N mutation of TMC1, the same mutation causing hearing loss in a family we studied. We compared the mutation-linked genetic marker genotypes and haplotypes, and found they were different between the two families. This indicates that the mutations probably arose independently, not from a common founder.
8. We performed a genotypic survey for DFNB7/B11 deafness caused by TMC1 mutations in Pakistan. We identified several novel mutations and showed that TMC1 mutations account for approximately 3.4% of severe to profound, prelingual-onset deafness in Pakistan.
1. 我们正在研究跨膜通道样(TMC)基因1和2。我们产生了分离Tmc1和Tmc2的敲除(空)等位基因的小鼠。我们正在描述他们突变的听觉和前庭(平衡)表型。敲除两种基因等位基因纯合的小鼠耳聋,前庭功能异常。Tmc1基因敲除等位基因纯合子的小鼠是失聪的。Tmc2敲除等位基因纯合子的小鼠具有正常的听力和平衡。这些结果表明Tmc1和Tmc2都是正常前庭功能(平衡)所必需的,而只有Tmc1是听力所必需的。我们在敲除小鼠中使用LacZ报告基因来研究遗传相互作用可能发生的位置。Tmc1报告基因在所有前庭终末器官的毛细胞中表达,而Tmc2报告基因在壶腹嵴的毛细胞中表达。我们现在使用毛细胞标记物来确定这些基因是否在1型或2型毛细胞中表达,或者两者都表达。我们正在与Charley Della Santina博士合作,测量小鼠的前庭-眼反应,以确定它们的异常平衡和步态是否是由于半圆形管(嵴)或前庭系统其他部分的功能异常。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Auditory function associated with Col11a1 haploinsufficiency in chondrodysplasia (cho) mice.
软骨发育不良 (cho) 小鼠的听觉功能与 Col11a1 单倍体不足相关。
- DOI:10.1016/s0378-5955(02)00736-0
- 发表时间:2003
- 期刊:
- 影响因子:2.8
- 作者:Szymko-Bennett,YvonneM;Kurima,Kiyoto;Olsen,Bjorn;Seegmiller,Robert;Griffith,AndrewJ
- 通讯作者:Griffith,AndrewJ
Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction.
- DOI:10.1016/j.anl.2014.04.001
- 发表时间:2014-10
- 期刊:
- 影响因子:1.7
- 作者:Nakanishi, Hiroshi;Kurima, Kiyoto;Kawashima, Yoshiyuki;Griffith, Andrew J.
- 通讯作者:Griffith, Andrew J.
Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis.
- DOI:10.1371/journal.pgen.1002309
- 发表时间:2011-09
- 期刊:
- 影响因子:4.5
- 作者:Hertzano R;Elkon R;Kurima K;Morrisson A;Chan SL;Sallin M;Biedlingmaier A;Darling DS;Griffith AJ;Eisenman DJ;Strome SE
- 通讯作者:Strome SE
Col11a1 and Col11a2 mRNA expression in the developing mouse cochlea: implications for the correlation of hearing loss phenotype with mutant type XI collagen genotype.
发育中的小鼠耳蜗中 Col11a1 和 Col11a2 mRNA 表达:听力损失表型与突变型 XI 胶原基因型相关性的影响。
- DOI:10.1080/00016480410016162
- 发表时间:2004
- 期刊:
- 影响因子:1.4
- 作者:Shpargel,KarlB;Makishima,Tomoko;Griffith,AndrewJ
- 通讯作者:Griffith,AndrewJ
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Andrew J Griffith其他文献
Andrew J Griffith的其他文献
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{{ truncateString('Andrew J Griffith', 18)}}的其他基金
ANALYSIS OF FAMILIES WITH INHERITED CRANIOFACIAL AND INNER EAR MALFORMATIONS
遗传性颅面和内耳畸形家族的分析
- 批准号:
6113400 - 财政年份:1998
- 资助金额:
$ 229.77万 - 项目类别:
ANALYSIS OF FAMILIES WITH INHERITED CRANIOFACIAL AND INNER EAR MALFORMATIONS
遗传性颅面和内耳畸形家族的分析
- 批准号:
6297106 - 财政年份:1998
- 资助金额:
$ 229.77万 - 项目类别:
ANALYSIS OF FAMILIES WITH INHERITED CRANIOFACIAL AND INNER EAR MALFORMATIONS
遗传性颅面和内耳畸形家族的分析
- 批准号:
6274634 - 财政年份:1997
- 资助金额:
$ 229.77万 - 项目类别:
ANALYSIS OF FAMILIES WITH INHERITED CRANIOFACIAL AND INNER EAR MALFORMATIONS
遗传性颅面和内耳畸形家族的分析
- 批准号:
6244594 - 财政年份:1997
- 资助金额:
$ 229.77万 - 项目类别:
Molecular Genetic Analysis of the Mouse Twirler Mutation
小鼠 Twirler 突变的分子遗传学分析
- 批准号:
6431993 - 财政年份:
- 资助金额:
$ 229.77万 - 项目类别:
ANALYSIS OF FAMILIES WITH INHERITED CRANIOFACIAL AND INNER EAR MALFORMATIONS
遗传性颅面和内耳畸形家族的分析
- 批准号:
6303536 - 财政年份:
- 资助金额:
$ 229.77万 - 项目类别:
Clinical Analysis Of Disorders Of Hearing And Balance
听力和平衡障碍的临床分析
- 批准号:
7130266 - 财政年份:
- 资助金额:
$ 229.77万 - 项目类别:
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