Oculocerebrorenal syndrome of Lowe: Three mutations in the OCRL1 gene derived from three patients with different phenotypes

The oculocerebrorenal syndrome of Lowe (OCRL) is an X‐linked multisystem disorder with major abnormalities of eyes, nervous system, and kidneys. Clinical manifestations include congenital cataract, mental retardation, and renal tubular dysfunction. A gene (OCRL1) responsible for OCRL was identified by positional cloning and its product OCRL‐1 protein was shown to be a phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] 5‐phosphatase localized to the Golgi apparatus. We describe three mutations in OCRL1, one in a patient with severe phenotype and two in patients with moderate phenotype (degree of mental retardation and musculoskeletal abnormalities). The patient with severe phenotype had a G‐to‐A transition at nucleotide (nt) 1,739, causing an Arg‐to‐Gln substitution at amino acid 577, and one patient with moderate phenotype had a C‐to‐G transversion at nt 1,812, leading to a His‐to‐Gln substitution at amino acid 601. Both Arg‐577 and His‐601 are encoded by exon 15 and are probably important for proper function of this protein, since these are conserved in various enzymes catalyzing dephosphorylation of inositol compounds. In the other patient with the moderate phenotype, there was a G‐to‐A transition at nt 2,797 located at the 3′‐end of exon 22. This substitution led to a skip of the same exon as well as conversion of codon‐930 from GCT (Ala) to ACT (Thr) in the normal‐size transcript. When we measured the enzyme activity in skin fibroblasts from the three patients, the activity was less than 10%, compared to findings in normal controls. Western blot analysis showed absence or severe decrease in OCRL‐1 protein in cell lysates derived from these patients. Am. J. Med. Genet. 77:348–355, 1998. © 1998 Wiley‐Liss, Inc.