title: Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: the pitfalls of homozygosity mapping.
abstract: Retinitis pigmentosa is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. At least 28 genes and loci have been implicated in nonsyndromic autosomal recessive retinitis pigmentosa. Here we report two extended and highly consanguineous families segregating early onset retinitis pigmentosa. Despite the consanguinity in both families, we found allelic heterogeneity in one of them, in which affected individuals were compound heterozygotes for two different mutations of the CRB1 gene. In the second family we found evidence for locus heterogeneity. A novel homozygous mutation of RDH12 was found in only 14 of 17 affected individuals in this family. Our data indicate that in the other affected individuals the disease is caused by a different gene/s. These findings demonstrate that while homozygosity mapping is an efficient tool for identification of the underlying mutated genes in inbred families, both locus and allelic heterogeneity may occur even within the same consanguineous family. These observations should be taken into account, especially when studying common and heterogeneous recessive genetic conditions.
authors.affiliation: Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Benayoun
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.forename: Noa
authors.initials: N
authors.lastname: Auslender
authors.forename: Anan H
authors.initials: AH
authors.lastname: Abbasi
authors.forename: Leah
authors.initials: L
authors.lastname: Rizel
authors.forename: Yasir
authors.initials: Y
authors.lastname: Hujeirat
authors.forename: Ihsan
authors.initials: I
authors.lastname: Salama
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Garzozi
authors.forename: Stavit
authors.initials: S
authors.lastname: Allon-Shalev
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000483:Alleles; D000595:Amino Acid Sequence; D018912:Arabs / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007557:Israel; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012162:Retinal Degeneration / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C448939:CRB1 protein, human; D017931:DNA Primers; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000429:Alcohol Oxidoreductases; C489649:RDH12 protein, human