Konigsmark et al. (1971) studied 3 families with low frequency hearing loss in an autosomal dominant pedigree pattern.
In a large Costa Rican family, Leon et al. (1981) described many cases of low frequency autosomal dominant ... Konigsmark et al. (1971) studied 3 families with low frequency hearing loss in an autosomal dominant pedigree pattern. In a large Costa Rican family, Leon et al. (1981) described many cases of low frequency autosomal dominant deafness which differed from that previously reported in its earlier onset (first decade) and its progression to more profound deafness. Although the audiometric results indicated an apical initiation of the pathology, as might result from endolymphatic hydrops, presumably produced by alterations in the stria vascularis or from labyrinthine otosclerosis, no bone histology was available to identify the precise structures affected. In later studies, Leon et al. (1992) indicated that the deafness was primary (i.e., nonsyndromal) and postlingual (with onset at about age 10 years, after language and speaking were learned). By age 30, intelligence, fertility, and life expectancy were normal. The family traced its ancestry to an affected founder by the name of Monge, who was born in Costa Rica in 1754. Low frequency hearing loss is said to occur in several sensorineural hearing disorders such as Meniere disease, myxedema, and inner ear malformations, and in conductive hearing disorders resulting from either fixation or partial disruption of the ossicular chain (Parving, 1984).
The form of autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive hearing loss in the large Costa Rican kindred studied by Leon et al. (1981, 1992) was designated DFNA1. Lynch et al. (1997) mapped the DFNA1 gene in this ... The form of autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive hearing loss in the large Costa Rican kindred studied by Leon et al. (1981, 1992) was designated DFNA1. Lynch et al. (1997) mapped the DFNA1 gene in this kindred to a region of 1 cM on 5q31 by linkage analysis and constructed a complete 800-kb bacterial artificial chromosome (BAC) contig of the linked region. They compared the sequences of these BACs with known genes and expressed sequence tags (ESTs) from all available databases. A previously unidentified human gene homologous to the Drosophila gene 'diaphanous' and a mouse gene was revealed by the genomic sequence of 3 BACs. The human diaphanous gene (602121) was screened for mutations in members of the Costa Rican M family by means of SSCP analysis. Sequencing of variant bands revealed a guanine-to-thymine substitution in the splice donor of the penultimate exon of DFNA1 in affected members of the M kindred (602121.0001). The base substitution disrupted the canonical splice donor sequence AAGgtaagt and resulted in insertion of 4 nucleotides in the transcript, a frameshift, and loss of the C-terminal 32 amino acids of the protein. All 78 affected members of the M kindred were heterozygous for the mutation. The site was wildtype in 330 control individuals with normal hearing (660 chromosomes) of the following ancestries: 12 Costa Ricans unrelated to the M family, 94 Latin Americans from other countries, 32 Spanish, 154 Europeans (other than Spanish) and North Americans of European ancestry, and 38 African Americans. By RT-PCR of cochlear RNA using PCR primers that amplify the region of the gene that harbored the mutation in family M, Lynch et al. (1997) confirmed expression of human diaphanous in the cochlea. The authors speculated that the biologic role of this human diaphanous homolog in hearing is likely to be the regulation of actin polymerization in hair cells of the inner ear.