Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder chara cterized by major abnormalities of eyes, nervous system, and kidneys. Mutat ions in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4,5-biphosphate (PtdIns[4,5]P2) 5-phosphatase. We h ave examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the ne w mutations, two nonsense mutations (R317X and E558X) and three other frame shift mutations caused premature termination of the protein. A missense mut ation, R483G, was located in the highly conserved PtdIns(4,5)P2 5-phosphata se domain. Finally, one frameshift mutation, 2733delC, modifies the C-termi nal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluste r in exons 11-15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This obse rvation has direct implications for genetic counseling of Lowe syndrome fam ilies.