Sensorineural hearing loss is genetically heterogeneous. Here we report that mutations in CIB2, encoding a Ca2+- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). There is one mutation of CIB2 that is a prevalent cause of DFNB48 deafness in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In rodents, CIB2 is localized in the mechanosensory stereocilia of inner ear hair cells and in retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of Ca2+ binding, CIB2 significantly decreased the ATP-induced Ca2+ responses in heterologous cells, while DFNB48 mutations altered CIB2 effects on Ca2+ responses. Furthermore, in zebrafish and Drosophila, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We show that CIB2 is a new member of the vertebrate Usher interactome.

Autosomal recessive hypotrichosis (LAH3) is a rare hair disorder characterized by sparse hair on scalp and the rest of the body of affected individuals. Recently mutations in a G protein-coupled receptor gene, P2RY5, located at LAH3 locus, have been reported in several families with autosomal recessive hypotrichosis simplex and woolly hair. For the present study, 22 Pakistani families with autosomal recessive hypotrichosis were enrolled. Genotyping using microsatellite markers linked to three autosomal recessive forms of hypotrichosis (LAH1, LAH2, LAH3) showed the linkage of 2 families to the LAH2 locus and 14 to the LAH3 locus. The remaining 6 families were not linked to any of the three loci. Families linked to LAH3 locus were further subjected to screening of the P2RY5 gene with direct DNA sequencing. Three previously reported variants, c.69insCATG (p.24insHfs52), c.188A > T (p.D63V) and c.565G > A (p.E189K) were observed in eight families. Four novel nonsynonymous sequence variants, c.8G > C (p.S3T), c.36insA (p.D13RfsX16), c.160insA (p.N54TfsX58) and c.436G > A (p.G146R) were found to segregate within six families.

Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss.