Anti-DNMBP monoclonal antibody, clone FQS21126

Genetic association of the dynamin binding protein gene (DNMBP) on chromosome 10 with late-onset Alzheimer's disease (AD) was reported among Japanese. Here, we assessed the genetic role of DNMBP in an extended Belgian AD group using a gene-wide association approach. A total of 18 SNPs across the DNMBP locus were genotyped in 555 late-onset AD patients and 638 healthy control individuals. Significant associations were observed for two SNPs (rs3740057 and rs10883421). Haplotype analysis identified association with haplotype blocks in the 3' region of DNMBP comprising rs2862919, rs11190302, rs10509739, rs2256700 and comprising rs3740057 and rs6584331. Stratification for APOE 0 status showed that association was only present in the APOE epsilon 4 negative subgroup. Sliding-window analyses provided further evidence for association with the 3'-end of DNMBP both for the total and for the APOE epsilon 4 negative group. Taken together our findings underscore a role for DNMBP in the genetic risk for late-onset AD in the Belgian Population (C) 2008 Elsevier Inc. All rights reserved.

Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP: nonsense variant c.811C >T (p.Arg271*) in large family F385 (nine affected individuals; LOD score = 5.18 at theta = 0), frameshift deletion c.2947_2948de1 (p.Asp983*) in family F372 (two affected individuals), and frameshift variant c.2852_2855de1 (p.Thr951Metfs*41) in family F3 (one affected individual). The phenotypes of all affected individuals include infantile-onset cataracts. RNAi-mediated knockdown of the Drosophila ortholog still life (sit), enriched in lens-secreting cells, affects the development of these cells as well as the localization of E-cadherin, alters the distribution of septate junctions in adjacent cone cells, and leads to a similar to 50% reduction in electroretinography amplitudes in young flies. DNMBP regulates the shape of tight junctions, which correspond to the septate junctions in invertebrates, as well as the assembly pattern of E-cadherin in human epithelial cells. E-cadherin has an important role in lens vesicle separation and lens epithelial cell survival in humans. We therefore conclude that DNMBP loss-of-function variants cause infantile-onset cataracts in humans.