Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation - PubMed

Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation

Y Bykhovskaya et al. Am J Med Genet. 1998.

Abstract

The relationship between mitochondrial genotype and clinical phenotype is complicated in most instances by the heteroplasmic nature of pathogenic mitochondrial mutations. We have previously shown that maternally inherited hearing loss in a large Arab-Israeli kindred is due to the homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with this mutation have phenotypes ranging from profound hearing loss to completely normal hearing, and we have shown that there is genetic and biochemical evidence for nuclear gene involvement in this family [Bu et al., 1993: Genet Epidemiol 9:27-44; Guan et al., 1996: Hum Mol Genet 5:963-971]. To identify such a nuclear locus, two candidate genes were excluded through linkage analysis and sequencing, and a genome-wide linkage search in family members who all have the identical homoplasmic mitochondrial mutation, but differ in their hearing status, was performed. In two stages a total of 560 polymorphic genetic markers was genotyped, and the data were analyzed under model-dependent and model-free assumptions. No chromosomal region was identified as a major contributor to the phenotypic expression of the mitochondrial mutation. Thus, in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in the similar environment of a small village, the penetrance of the mitochondrial mutation appears to depend on the interaction of multiple nuclear genes.

Similar articles

• Candidate locus for a nuclear modifier gene for maternally inherited deafness.

  Bykhovskaya Y, Estivill X, Taylor K, Hang T, Hamon M, Casano RA, Yang H, Rotter JI, Shohat M, Fischel-Ghodsian N. Bykhovskaya Y, et al. Am J Hum Genet. 2000 Jun;66(6):1905-10. doi: 10.1086/302914. Epub 2000 Apr 27. Am J Hum Genet. 2000. PMID: 10788333 Free PMC article.

• Mitochondrial mutation associated with nonsyndromic deafness.

  Fischel-Ghodsian N, Prezant TR, Fournier P, Stewart IA, Maw M. Fischel-Ghodsian N, et al. Am J Otolaryngol. 1995 Nov-Dec;16(6):403-8. doi: 10.1016/0196-0709(95)90078-0. Am J Otolaryngol. 1995. PMID: 8572257

• Modifier locus for mitochondrial DNA disease: linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness.

  Bykhovskaya Y, Yang H, Taylor K, Hang T, Tun RY, Estivill X, Casano RA, Majamaa K, Shohat M, Fischel-Ghodsian N. Bykhovskaya Y, et al. Genet Med. 2001 May-Jun;3(3):177-80. doi: 10.1097/00125817-200105000-00005. Genet Med. 2001. PMID: 11388757

• [Modifier factors influencing the phenotypic manifestation of the deafness associated mitochondrial DNA mutations].

  YANG AF, ZHENG J, LV JX, GUAN MX. YANG AF, et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2011 Apr;28(2):165-71. doi: 10.3760/cma.j.issn.1003-9406.2011.02.010. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2011. PMID: 21462128 Review. Chinese.

• Phenotypic variants of the deafness-associated mitochondrial DNA A7445G mutation.

  Maász A, Komlósi K, Hadzsiev K, Szabó Z, Willems PJ, Gerlinger I, Kosztolányi G, Méhes K, Melegh B. Maász A, et al. Curr Med Chem. 2008;15(13):1257-62. doi: 10.2174/092986708784534910. Curr Med Chem. 2008. PMID: 18537605 Review.

Cited by

• Mutations in the mitochondrial tRNA Ser(UCN) and in the GJB2 (connexin 26) gene are not modifiers of the age at onset or severity of hearing loss in Spanish patients with the 12S rRNA A1555G mutation.

  López-Bigas N, Rabionet R, Martinez E, Bravo O, Girons J, Borragan A, Pellicer M, Arbonés ML, Estivill X. López-Bigas N, et al. Am J Hum Genet. 2000 Apr;66(4):1465-7. doi: 10.1086/302870. Am J Hum Genet. 2000. PMID: 10739773 Free PMC article. No abstract available.

• A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction.

  Wang M, Liu H, Zheng J, Chen B, Zhou M, Fan W, Wang H, Liang X, Zhou X, Eriani G, Jiang P, Guan MX. Wang M, et al. J Biol Chem. 2016 Sep 30;291(40):21029-21041. doi: 10.1074/jbc.M116.739482. Epub 2016 Aug 12. J Biol Chem. 2016. PMID: 27519417 Free PMC article.

• Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

  Kullar PJ, Gomez-Duran A, Gammage PA, Garone C, Minczuk M, Golder Z, Wilson J, Montoya J, Häkli S, Kärppä M, Horvath R, Majamaa K, Chinnery PF. Kullar PJ, et al. Brain. 2018 Jan 1;141(1):55-62. doi: 10.1093/brain/awx295. Brain. 2018. PMID: 29182774 Free PMC article.

• [Mitochondrial hearing impairment. Background, genetic predisposition and possibilities for diagnosis].

  Riemann K, Pfister M, Blin N, Kupka S. Riemann K, et al. HNO. 2004 Jun;52(6):503-9. doi: 10.1007/s00106-003-0993-9. HNO. 2004. PMID: 15241512 Review. German.

• Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity.

  Gao Z, Chen Y, Guan MX. Gao Z, et al. J Otol. 2017 Mar;12(1):1-8. doi: 10.1016/j.joto.2017.02.001. Epub 2017 Feb 11. J Otol. 2017. PMID: 29937831 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Wiley

• Medical

  • MedlinePlus Health Information