TY - JOUR
T1 - Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family
AU - Hmani-Aifa, Mounira
AU - Benzina, Zeineb
AU - Zulfiqar, Fareeha
AU - Dhouib, Houria
AU - Shahzadi, Amber
AU - Ghorbel, Abdelmonem
AU - Rebaï, Ahmed
AU - Söderkvist, Peter
AU - Riazuddin, Sheikh
AU - Kimberling, William J.
AU - Ayadi, Hammadi
N1 - Funding Information:
We thank the family members for their invaluable participation and cooperation. We are thankful to Pr Saber Masmoudi for his critical reading of the paper. We also thank Salma ben Salem for her help in table and figure perfection. This study was supported by Ministère de l’Enseignement Supérieur, de la Recherche Scientifique et de la Technologie, Tunisia, and the European Commission FP6 Integrated Project EUROHEAR, LSHG-CT-20054-512063. Support for WJ Kimberling is from Foundation Fighting Blindness (BR-GE-0606-0343) and the National Institutes of Deafness and Communication Disorders (P01 DC01813).
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2008.167
DO - 10.1038/ejhg.2008.167
M3 - Article
C2 - 18854872
AN - SCOPUS:62849083861
SN - 1018-4813
VL - 17
SP - 474
EP - 482
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 4
ER -