Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family

Abstract

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23 -24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network

“…The locus for Usher syndrome type 2b, which harbored the CACNA1D gene, has recently been withdrawn. 70,71 …”

A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

“…The co-occurrence of Pde6b and Adgrv1 mutations has been reported in an USH human family [52]. In this case, some offspring of the family with both mutated genes exhibit a more severe ocular phenotype than the other members with only a mutation of Adgrv1.…”

Usher Syndrome: Genes, Proteins, Models, Molecular Mechanisms, and Therapies

“…The gene for USH2B was once considered to be NBC3 (sodium bicarbonate cotransporter) www.intechopen.com Hearing Loss 296 (Bok et al, 2003). However, further study of the consanguineous Tunisian family carrying the USH2B locus demonstrates that mixed mutations in the GPR98 and PDE6B genes are responsible for the disease manifestation in the family and, thus, the USH2B locus was withdrawn (Hmani-Aifa et al, 2009). Moreover, a novel USH2 locus has recently been localized on the chromosome 15q, though the underlying gene has not been identified so far (Ben Rebeh et al, 2008).…”

“…Currently, eleven loci have been identified (Hereditary hearing loss homepage and Hmani-Aifa et al, 2009), and nine genes on these loci are known. Among these genes, five are involved in USH1, three in USH2 and one in USH3 (Reiners et al, 2006;Williams, 2008;Millan et al, 2011).…”