IDENTIFICATION OF 2 NOVEL MUTATIONS IN THE OCRL1 GENE IN JAPANESE FAMILIES WITH LOWE-SYNDROME

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disor der with features of congenital cataracts, Fanconi syndrome of the ren al tubule, and mental retardation. The OCRL1 gene has been positionall y cloned and shown to encode a phosphatidylinositol 4,5-biphosphate-5- phosphatase. OCRL is thus thought to be an inborn err-or of inositol p olyphosphate metabolism. We analyzed the gene in two Japanese OCRL pat ients and their families by DNA sequencing and mismatch polymerase cha in reaction (PCR) followed by restriction digestion. A novel nonsense mutation (C1399T) replacing the glutamine of codon 391 (Gln 391 Stop) was identified in exon 12 in 1 patient and also in his mother. A novel missense mutation (C1743G) was identified in exon 15 in the second pa tient, his mother and maternal grandmother, The missense mutation pred icts a substitution of serine for arginine (Ser 505 Arg) in a domain h ighly conserved among the inositol-5-phosphatase family. Our observati ons expand the range of OCRL1 mutations that cause Lowe syndrome, and will be useful for genetic counseling in these two families.