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.