From lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes

Abstract

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.

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

“…10 Recently however, two different OCRL mutations each causing both Dent disease 2 and Lowe syndrome even in the same family have been described. 20 In short, Dent's disease seems to be characterized by a genetic and phenotypic heterogeneity.…”

Clinical utility gene card for: Lowe syndrome

“…The gold standard is analysis of functional consequences of the respective OCRL variant in cell models, performed in a few laboratories in the world. 3,[5][6][7] In case of suspected splice site variants, OCRL mRNA should be analyzed.…”

“…3,8,9 Other ocular findings include microphthalmia, enophtalmos and glaucoma, the latter developing in the first three decades in 50-60% of the patients. About 25% of Lowe syndrome patients have corneal scarring and keloids.…”

“…In a large series, 6 out of 136 families with an OCRL variant were classified as Dent-2. 3 There have been incidental reports of Lowe syndrome and Dent-2 in patients harboring the same variant, even within one family. 3 …”