Genetic analysis of a four

Usher syndrome (USH) named after the British ophthalmologist Charles Usher [1] is the most common hereditary form of combined blindness and deafness [2]. It is a rare disorder with an incidence of 3.5/100,000 in Scandinavia [3] to 4.4/100,000 in the USA [4]. It shows an autosomal recessive mode of inheritance. According to clinical symptoms, USH is classified into three types: USH type I, USH type II and USH type III. USH type I is the most severe form and is characterized by severe to profound congenital sensorineuronal deafness, constant vestibular dysfunction (balance deficiency) and prepubertal onset of retinitis pigmentosa (RP). USH type II has a congenital mild to moderate hearing loss, normal vestibular responses, and RP during the second decade of life. USH type III has a progressive hearing loss, variable vestibular problems and variable RP [5]. USH type I is genetically heterogeneous with seven known loci: USH1A on chromosome 14q [6], USH1B on chromosome 11q [7], USH1C on chromosome 11p15.1 [8], USH1D on chromosome 10q21-22 [9], USH1E on chromosome 21q21 [10], USH1F on chromosome 10 [11] and USH1G on chromosome 17q24-25 [12]. USH1B is the most common subtype and accounts for about 70% of all type I cases [13]. Of seven loci for USH type I, genes for only five loci (USH1B, USH1C, USH1D, USH1F, and USH1G) have been isolated so far. USH1B is known to be caused by mutations in an unconventional myosin, the motor protein myosin VIIA [14]. Atypical USH, in which the hearing loss is progressive, is also known to be caused by mutations in the myosin VIIA [15]. USH1C, USH1D, USH1F, and USH1G are caused by mutations in PDZ73 (harmonin), CDH23 (cadherin 23), PCDH15 (Procadherin), and SANS genes, respectively [16-19]. USH type II is genetically heterogeneous with three known loci: USH2A on chromosome 1q41 [20], USH2B on chromosome 3p22-24.2 [21], and USH2C on chromosome 5q14.3-21.3 [22]. The USH2A gene coding for extracellular protein usherin has been shown to be responsible for disease phenotype linked to the USH2A locus [23]. Weston et al. [24] have recently isolated the gene, VLGR1 (MASS1) for the USH2C locus. A single locus, USH3 has been mapped to chromosome 3q21-25 for USH type III [25]. Joensuu et al. [26] have identified the gene for this locus, which codes for a cellcell adhesion protein called clarin-1. Genetic analysis of USH has been carried out in patients from several countries [5-35]. However, there is no report on the genetic analysis of any Indian family with USH. We report here genetic analysis of a four generation Indian family with members suffering from USH for the first time. Haplotype analysis suggested mapping of this family to the USH1B locus. DNA sequence analysis identified a novel insertion mutation in the MYO7A gene in this family. ©2004 Molecular Vision