1. ¹Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie de Sfax, Tunisie
2. ²Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Tunisie
3. ³Service d'Ophtalmologie, CHU Habib Bourguiba, Sfax, Tunisie
4. ⁴Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
5. ⁵Service d'ORL, CHU Habib Bourguiba, Sfax, Tunisie
6. ⁶Unité de Bioinformatique, biostatistique et signalisation, Centre de Biotechnologie de Sfax, Tunisie
7. ⁷Division of Cell Biology, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Linköping, Sweden
8. ⁸Center for Hereditary Communication Disorders, Boys Town National Research Hospital (BTNRH), Omaha, NE, USA

Correspondence: Dr M Hmani-Aifa, Unit of Diagnosis and Therapy Targets for Human pathology, Centre of Biotechnology of Sfax, Route sidi Mansour Km6, BP '1177', Sfax-Tunisia 3018, Tunisia. Tel: +216 74 871 816 1080; Fax: +216 74 875 818; E-mail: hmanimounira@yahoo.fr

Received 4 March 2008; Revised 6 August 2008; Accepted 27 August 2008; Published online 15 October 2008.

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.