OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability.

BACKGROUND/AIMS: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. METHODS: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed. RESULTS: Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. CONCLUSIONS: OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants.

Increased cardiovascular risk profile and mortality in kidney allograft recipients with post-transplant diabetes mellitus in Spain.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is associated with poorer outcomes in kidney transplantation (KT) but little information exists about the evolution of traditional cardiovascular risk (CVR) factors under this disorder. METHODS: We retrospectively analysed CVR factors at 3, 12 and 24 months of follow-up and mortality at three yr in 3365 KT performed in Spain during the years 1990, 1994 and 1998 with a functioning graft after the first year. Three groups were considered: (i) (PTDM, n, 251), (ii) diabetes mellitus as primary disease (DM, n = 156) and (iii) the remaining patients (controls, n = 2958). RESULTS: Recipient age, weight and body mass index (BMI) were higher in PTDM than in the other groups (p < 0.0001), with a lower increase of body weight during follow-up (p < 0.003). PTDM patients showed higher total-cholesterol levels than controls at one (p < 0.01) and two yr (p < 0.0009), and higher triglyceride levels than the other groups during follow-up (p < 0.002). Compared with Controls, PTDM patients had significantly higher systolic blood pressure at one (p < 0.001) and two yr (p < 0.005). Diastolic blood pressure was higher in PTDM and controls (p < 0.001), while pulse pressure was higher in PTDM and DM patients (p < 0.0001) during follow-up. Using Cox proportional hazards analysis, PTDM correlated with total mortality (RR = 1.55; range 1.05-2.3; p < 0.02) but not with cardiovascular mortality. CONCLUSIONS: In Spanish KT recipients with graft function after one yr, PTDM is associated with a worse traditional CVR profile and a higher overall mortality. Although short-term cardiovascular mortality remains similar, better control of CVR factors is mandatory to prevent long-term cardiovascular mortality inherent to this population.