| MSUDF1 family is a mid-Michigan family of English descent with a form of nonsyndromic, genetic, late-onset, bilateral, progressive, sensorineural hearing loss. This locus was designated DFNA20 locus by the nomenclature committee of the Human Genome Organization in 1999 and contains a gene that is responsible for a hearing loss of dominant inheritance. It is the 20th locus discovered for the autosomal dominant hearing loss.; The gene for the hearing loss in this MSUDF1 family was mapped using a strategy of whole genome screening after the exclusion of known hearing loss loci. Positive linkage was found to the microsatellite marker, D17S784, on 17q25 near the telomere of the long arm (q) of chromosome 17. Haplotype analysis using additional markers on 17q25 defines the obligate region to an approximately 5.5 cM.; Ten possible candidate genes in this critical region were analyzed, these are CNCNG, GRIN2C, FKHL13, ACTG1, SPARC, ERBA2L, ARHGDAI, P4HB, DNEL1 and GALR2. CNCNG, GRIN2C, FKHL13, ACTG1 are clearly fine-mapped outside of the DFNA20 locus using two RH map panels, G3 and TNG4 from Stanford. SPARC and ERBA2L are spurious or incorrectly assigned on 17q25. The rest of the candidates, ARHGDAI, P4HB, DNEL1, GALR2 were sequenced including the intron/exon boundary. These genes contain no mutations and were ruled out as the causative gene(s).; As the sequenced data from HGP and Celera were obtained, new microsatellite markers and SNPs were identified and used to narrow the DFNA20 interval to a region of about 1.5 megabases and a partial physical contig of approximately 1 megabases was also constructed.; This interval contained no known genes but has many novel partial transcripts. To select potentially important genes, ear expressed transcripts were identified with the help of a human cochlear cDNA library made at NIDCD and a mouse cochlear gene expression database constructed at the Corey lab at Harvard Medical School. Four interesting transcripts were found. These transcripts were characterized by multiple tissue northern blot in order to look for the tissue expression profile. Full-length transcripts were compiled by sequencing I. M. A. G. E clones and using EST data from HGP. The four transcripts were then sequenced on affected chromosome first. Any suspect changes were rechecked on the somatic hybrid carrying the normal chromosome. No significant changes were found. These four ear expressed transcripts are also excluded from consideration as causative gene(s) in this MSUDF1 family. |
