Carrier assessment in families with Lowe oculocerebrorenal syndrome: Novelmutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination

Lowe oculocerebrorenal syndrome (OCRL) (MIM 309000) is a rare X-linked mult isystem disorder characterized by congenital cataracts, muscular hypotonia, areflexia, mental retardation, maladaptive behavior, renal tubular dysfunc tion, vitamin-D-resistant rickets, and scoliosis. The underlying gene OCRL1 is located on chromosome Xq25-q26 and contains 24 exons. It encodes a 105- kDa phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P-2) 5-phosphatase th at is localized to the Golgi complex. To confirm the clinical diagnosis and to assess the carrier state of female relatives for genetic counseling we examined 6 independent patients and their families (a total of 23 individua ls) using an improved mutation screening strategy for the OCRL1 gene by seq uencing of large PCR amplicons. Four novel and two known mutations were ide ntified: three premature terminations caused by either frameshift mutations (1899insT in exon 17 and 2104-2105delGT in exon 18) or a nonsense mutation (1399C > T in exon 12), two missense mutations (1676G > A and 1754C > T in exon 15), and a 6-bp deletion (1609-1614delAAGTAT in exon 14). An ophthalm ological examination was performed in all patients and 14 female relatives. All genotypically proven carrier females showed characteristic lenticular opacities, while all proven noncarriers were lacking this phenotypic findin g. The results confirm that ophthalmological evaluation is an apparently re liable first-line method to ascertain the carrier state in Lowe oculocerebr orenal syndrome. The high expressivity of lenticular symptoms in OCRL1 gene carriers is consistent with the hypothesis that (PtdIns[4,5]P-2) 5-phospha tase activity has low functional reserve capacity for maintaining a balance d homeostasis of lenticular metabolism. (C) 2000 Academic Press.