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Candidate locus for a nuclear modifier gene for maternally inherited deafness
Y Bykhovskaya1, X Estivill, K Taylor
1Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA, USA.
American Journal of Human Genetics
|May 2, 2000
Summary
Mitochondrial A1555G mutation causes deafness, but requires nuclear gene interaction. A specific chromosomal region shows linkage, suggesting it harbors a key modifier gene influencing hearing loss in diverse populations.
Area of Science:
- Genetics
- Mitochondrial Biology
- Otolaryngology
Background:
- Maternally inherited deafness linked to the A1555G mutation in mitochondrial 12S ribosomal RNA (rRNA) gene.
- Phenotypic expression of this mutation is influenced by environmental factors like aminoglycosides and genetic modifiers.
- Previous studies suggested nuclear gene involvement but failed to identify a major locus.
Purpose of the Study:
- To investigate nuclear modifier genes contributing to sensorineural deafness in families with the A1555G mitochondrial mutation.
- To identify specific chromosomal regions linked to the deafness phenotype in diverse ethnic groups.
Main Methods:
- Genome-wide screening and linkage analysis (parametric and nonparametric) were performed on 10 Spanish and Italian families.
- Analysis included 35 individuals with the A1555G mutation and sensorineural deafness.
- Data was combined with a previously studied Arab-Israeli pedigree.
Main Results:
- Parametric analysis did not identify linkage to a single autosomal locus.
- Nonparametric analysis indicated a suggestive linkage to the chromosomal region around marker D8S277.
- A combined maximized allele-sharing LOD score of 3.1 across Arab-Israeli, Spanish, and Italian families strongly supports this linkage.
Conclusions:
- The A1555G mitochondrial mutation's deafness penetrance is likely influenced by multiple nuclear genes.
- The chromosomal region near D8S277 is a strong candidate for harboring the first identified human nuclear modifier gene for a mitochondrial DNA disorder.
- This modifier locus appears to be conserved across Arab-Israeli, Spanish, and Italian populations.