Mutations of OCRL1 are associated with both the Lowe oculocerebrorenal syndrome, a multisystemic and Dent-2 disease, a renal tubulopathy. We have identified a mutation in 130 Lowe syndrome families and 6 affected by Dent-2 disease with 51 of these mutations being novel. No founding effect was evidenced for recurrent mutations. Two mutations initially reported as causing Dent-2 disease were identified in patients, including two brothers, presenting with Lowe syndrome thus extending the clinical variability of OCRL1 mutations. mRNA levels, protein content, and PiP(2) -ase activities were analyzed in patient's fibroblasts. Although mRNA levels were normal in cells harboring a missense mutation, the OCRL1 content was markedly lowered, suggesting that enzymatic deficiency resulted mainly from protein degradation rather than from a catalytic inactivation. Analysis of a splicing mutation that led to the elimination of the initiation codon evidenced the presence of shortened forms of OCRL1 that might result from the use of alternative initiation codons. The specific mapping of the frameshift and nonsense mutations, exclusively identified in exons 1-7 and exons 8-23, respectively, for Dent disease and Lowe syndrome together with the possible use of alternative initiation codons might be related to their clinical expression, that is, Lowe syndrome or Dent-2 disease.
The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n ¼ 2), or associated with another mutation at BBS1 (n ¼ 3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.
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