MUTATIONS ARE NOT UNIFORMLY DISTRIBUTED THROUGHOUT THE OCRL1 GENE IN LOWE-SYNDROME PATIENTS

Lowe syndrome (OCRL) is an X-linked disorder involving the eyes, kidne y, and nervous system that is caused by loss of function in the OCRL1 gene. OCRL1 contains 24 exons (23 of which are coding) and encodes a 1 05-kDa enzyme with phosphatidylinositol 4,5 bisphosphate (PtdIns[4,5]P -2) 5-phosphatase activity. We published previously (1,2) 13 different mutations in 15 patients. Here we report another 8 mutations in 10 fa milies. Four are missense mutations in highly conserved PtdIns(4,5)Pz 5-phosphatase domains, two are premature terminations caused by nonsen se mutations, and three others are premature terminations caused by fr ameshift mutations. One frameshift, a GT deletion in exon 21, has been observed previously in two unrelated Lowe syndrome patients, suggesti ng that it may be a relative ''hotspot'' for mutation in a disorder ma rked otherwise by allelic heterogeneity. We have also seen two other r ecurrent mutations. One is a nonsense mutation <(C)under bar GA> > <(T )under bar GA> in exon 22 observed in two patients and the second is a missense mutation CGA > CA in exon 15 present in two unrelated patien ts. These 21 distinct mutations we have found in 25 Lowe syndrome pati ents occur in only 9 of the 24 exons: 10, 12, 13, 14, 15, 18, 19, 21, and 22. interestingly missense mutations have occurred only in exons 1 2 through 15 in highly conserved residues among the phosphatidylinosit ol 5-phosphatases, These observations suggest useful strategies for mu tation screening in OCRL, (C) 1998 Academic Press.