Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton. Recently developed animal models have managed to recapitulate features of Lowe syndrome and Dent-2 disease, and revealed new insights into the underlying mechanisms of these disorders. The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients.

Genetic factors play an important part in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, a heterogeneous disorder characterised by defects in insulin action as well as insulin secretion [1]. Investigations of candidate genes for Type II diabetes have led to the identification of polymorphisms of several genes. Major genetic causes of this disease, however, remain elusive.Glucose-dependent sequestration of Ca 2+ into endoplasmic reticulum and its subsequent release play an important part in the control of intracellular Ca 2+ concentration, which regulates insulin secretion in pancreatic beta cells [2]. The active uptake of cytosolic Ca 2+ into endoplasmic reticulum is mediated by sarco(endo)plasmic reticulum Ca 2+ -transport ATPases (SERCAs) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca 2+ -transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca 2+ signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. Methods. In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. Results. We found four rare missense mutations [Exon 4: Gln 108 ®His (CAG®CAT), Exon 14: Val 648 ®Met (GTG®ATG) and Arg 674 ®Cys (CGC® TGC), and Exon 15: Ile 753 ®Leu (ATC®CTC)]. The patients with Gln 108 ®His, Val 648 ®Met and Arg 674 ®Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. Conclusion/interpretation. Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999.

The Lowe syndrome protein OCRL1 binds via IPIP27A to the F-BAR protein pacsin 2 to promote the biogenesis of trafficking intermediates containing the mannose 6-phosphate receptor at the trans-Golgi network and endosomes.