Gene Localization And A Novel Mutation Identified For Non-syndromic Hearing Loss

Hearing loss is a common sensory disorder in the human population, approximately 1 in 1000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Congenital deafness in at least 50% of subjects in developed countries is attributed to genetic defects. From 1990 till now, location and cloning of genes related to the hereditary hearing loss have developped so quickly. Hereditary hearing loss is a most common genetic disease in Otorhinolaryngology, also a paradigm of genetic heterogeneity. Although significant advances have been made, there is no doubt that more genes are to be discovered, and the function of the genes should be studied. Study on hereditary hearing loss genes and the molecular mechanism processes involved in the auditory system is important for both clarifying the molecular mechanism of heating and clinical prevention and cure of deafness.Hereditary heating loss is classified as nonsyndromic and syndromic types. Nonsyndromic hearing impairment can be subdivided by the mode of inheritance: 70% of causes are autosomal recessive (DFNB), 15～20% are autosomal dominant (DFNA), and less then 1% are X-linked (DFN) and mitochondrial inheritance. Remarkable progress has been made in the identification of new loci for nonsyndromic hearing impairment (NSHL) and in the cloning of deafness genes.In this research, we adopted classical linkage analysis method in mapping the locus for a Chinese DFNA family—NMG-L024 and screen the mutation。The Chinese family with six generations affected members are autosomal dominant progressive sensorineural hearing loss starting in the high frequencies then the mid and low frequencies.Whole genome scan and linkage analysis were performed, in which autosomal microsatellite markers were used. The disease gene causing hearing loss in this family was localized to the short arm of chromosome 7, in the 7p15.1—7p15.3. Fine mapping with nine STR in the region was performed, and six of them were used to do hyplotype. The result indicated that the crossing over happened in the affected numberⅣ∶2 in D7S629, andⅣ∶16,Ⅳ∶17 in D7S526. The disease gene was located within a 12 cM region between markers D7s629 and D7s526, with a maximum two-point lod (logarithm of differences) score of 5.39 (θ=0) at D7s2457.Within this region, DFNA5 gene located in 7p15 was considered to be a good candidate of disease-causing gene. By sequencing the coding and flanking region of DFNA5, a novel mutationⅣS8+4 A→G was detected, and no other mutation in any other part of DFNA5 has ever been found. Restriction digestion test in this mutation for whole family members and 100 normal control showed that the mutation was detected only in the cases of this family.Skipping of exon 8 in the DFNA5 gene has been determined through RT-PCR.However, till now, the function of the DFNA5 gene has not been known. More work should be done. We hope to find the truth.