Abstract
Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region.
Full Text
The Full Text of this article is available as a PDF (186.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bu X., Shohat M., Jaber L., Rotter J. I. A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: evidence from pedigree segregation analysis. Genet Epidemiol. 1993;10(1):3–15. doi: 10.1002/gepi.1370100102. [DOI] [PubMed] [Google Scholar]
- Bykhovskaya Y., Shohat M., Ehrenman K., Johnson D., Hamon M., Cantor R. M., Aouizerat B., Bu X., Rotter J. I., Jaber L. Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation. Am J Med Genet. 1998 Jun 5;77(5):421–426. doi: 10.1002/(sici)1096-8628(19980605)77:5<421::aid-ajmg13>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
- Casano R. A., Bykhovskaya Y., Johnson D. F., Hamon M., Torricelli F., Bigozzi M., Fischel-Ghodsian N. Hearing loss due to the mitochondrial A1555G mutation in Italian families. Am J Med Genet. 1998 Oct 12;79(5):388–391. [PubMed] [Google Scholar]
- Clerget-Darpoux F., Bonaïti-Pellié C., Hochez J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics. 1986 Jun;42(2):393–399. [PubMed] [Google Scholar]
- Estivill X., Govea N., Barceló E., Badenas C., Romero E., Moral L., Scozzri R., D'Urbano L., Zeviani M., Torroni A. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet. 1998 Jan;62(1):27–35. doi: 10.1086/301676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fischel-Ghodsian N. Mitochondrial mutations and hearing loss: paradigm for mitochondrial genetics. Am J Hum Genet. 1998 Jan;62(1):15–19. doi: 10.1086/301695. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guan M. X., Fischel-Ghodsian N., Attardi G. Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet. 1996 Jul;5(7):963–971. doi: 10.1093/hmg/5.7.963. [DOI] [PubMed] [Google Scholar]
- Hanis C. L., Boerwinkle E., Chakraborty R., Ellsworth D. L., Concannon P., Stirling B., Morrison V. A., Wapelhorst B., Spielman R. S., Gogolin-Ewens K. J. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161–166. doi: 10.1038/ng0696-161. [DOI] [PubMed] [Google Scholar]
- Kong A., Cox N. J. Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet. 1997 Nov;61(5):1179–1188. doi: 10.1086/301592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L., Lander E. S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995 Aug;57(2):439–454. [PMC free article] [PubMed] [Google Scholar]
- Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
- Pandya A., Xia X. J., Erdenetungalag R., Amendola M., Landa B., Radnaabazar J., Dangaasuren B., Van Tuyle G., Nance W. E. Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet. 1999 Dec;65(6):1803–1806. doi: 10.1086/302658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prezant T. R., Agapian J. V., Bohlman M. C., Bu X., Oztas S., Qiu W. Q., Arnos K. S., Cortopassi G. A., Jaber L., Rotter J. I. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet. 1993 Jul;4(3):289–294. doi: 10.1038/ng0793-289. [DOI] [PubMed] [Google Scholar]
- Torroni A., Cruciani F., Rengo C., Sellitto D., López-Bigas N., Rabionet R., Govea N., López De Munain A., Sarduy M., Romero L. The A1555G mutation in the 12S rRNA gene of human mtDNA: recurrent origins and founder events in families affected by sensorineural deafness. Am J Hum Genet. 1999 Nov;65(5):1349–1358. doi: 10.1086/302642. [DOI] [PMC free article] [PubMed] [Google Scholar]