Linkage Analysis of the X Chromosome in a Brazilian Family With Leber Hereditary Optic Neuropathy (LHON)

Abstract

Abstract: : Purpose: To identify an X–linked modifying gene that determines the expression of optic atrophy in a family affected with Leber hereditary optic neuropathy (LHON) harboring the 11778/ND4 homoplasmic mutation of mitochondrial DNA. LHON is a maternally inherited blinding disease caused by point mutations in the mitochondrial DNA. Although the mitochondrial mutation is transmitted to all the maternal offsprings the penetrance of optic atrophy is variable. Incomplete penetrance and male predominance in affected pedigrees and results of segregation analysis support the presence of an X–linked gene pre–disposing to the development of optic atrophy. Methods:Sixty–one individuals from a large Brazilian family of 265 members harboring a homoplasmic 11778/ND4 mutation on a J haplogroup were genotyped using 61 STRPs (single tandem repeat polymorphisms) on the X–chromosome with an average inter–marker distance of 5cM. Both two–point and multi–point parametric and non–parametric lod scores were calculated using the programs Gene Hunter and Linkage. Results:The multi–point non–parametric lod score was significant, being 3.0 with a "P" value of 0.007 for markers in the region Xq21 and the corresponding parametric lod score was 2.0, using the program Gene Hunter. Multipoint parametric lod scores at the same locus using Linkage program was 1.3. There was also another large region of non–exclusion on the X–chromosome in a 40cM region at Xq26–28. Conclusions: The results are suggestive of evidence for linkage to the X–chromosome at two loci. Lack of informativity due to sharing of alleles between the family members and presence of phenocopies are likely to result in the lower positive lod scores in the region of non–exclusion.

Keywords: mitochondria • gene mapping • gene modifiers