SPECTRUM OF MUTATIONS IN THE OCRL1 GENE IN THE LOWE OCULOCEREBRORENALSYNDROME

The oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorde r characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome. The OCRL1 gene, which, when mutated, is responsible for OCRL, encodes a 105-kD Golgi protein with phosphatidylinositol (4 ,5)bisphosphate (PtdIn[4,5]P-2) 5-phosphatase activity. We have examin ed the OCRL1 gene in 12 independent patients with OCRL and have found 11 different mutations. Six were nonsense mutations, and one a deletio n of one or two nucleotides that leads to frameshift and premature ter mination. In one, a 1.2-kb genomic deletion of exon 14 was identified. In four others, missense mutations or the deletion of a single codon were found to involve amino acid residues known to be highly conserved among proteins with PtdIns(4,5)P-2 5-phosphatase activity. All patien ts had markedly reduced PtdIns(4,5)P-2 5-phosphatase activity in their fibroblasts, whereas the ocrl1 protein was detectable by immunoblotti ng in some patients with either missense mutations or a codon deletion but was not detectable in those with premature termination mutations. These results confirm and extend our previous observation that the OC RL phenotype results from loss of function of the ocrl1 protein and th at mutations are generally heterogeneous. Missense mutations that abol ish enzyme activity but not expression of the protein will be useful f or studying structure-function. relationships in PtdIns(4,5)P-2 5-phos phatases.