naa a22 4500 53018544X CHVBK 20181026074445.0 cr unu---uuuuu 181026e20181004xx s 000 0 eng 10.1016/j.ajhg.2018.09.004 doi (SERVAL)BIB_EC45AA4ECA51 30290152 pmid 000446312200009 isiid Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts [Elektronische Daten] [M. Ansar, H.L. Chung, R.L. Taylor, A. Nazir, S. Imtiaz, M.T. Sarwar, A. Manousopoulou, P. Makrythanasis, S. Saeed, E. Falconnet, M. Guipponi, C.J. Pournaras, M.A. Ansari, E. Ranza, F.A. Santoni, J. Ahmed, I. Shah, K. Gul, G.C. Black, H.J. Bellen, S.E. Antonarakis] 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 θ = 0), frameshiftdeletion c.2947_2948del (p.Asp983 ∗ ) in family F372 (two affected individuals), and frameshift variant c.2852_2855del (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 (sif), 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 ∼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. Ansar M. aut Chung H.L. aut Taylor R.L. aut Nazir A. aut Imtiaz S. aut Sarwar M.T. aut Manousopoulou A. aut Makrythanasis P. aut Saeed S. aut Falconnet E. aut Guipponi M. aut Pournaras C.J. aut Ansari M.A. aut Ranza E. aut Santoni F.A. aut Ahmed J. aut Shah I. aut Gul K. aut Black G.C. aut Bellen H.J. aut Antonarakis S.E. aut American journal of human genetics 103/4(2018-10-04), 568-578 103:4<568-578 2018 103 1 article serval SERVAL 700 1- Ansar M. aut SERVAL 700 1- Chung H.L. aut SERVAL 700 1- Taylor R.L. aut SERVAL 700 1- Nazir A. aut SERVAL 700 1- Imtiaz S. aut SERVAL 700 1- Sarwar M.T. aut SERVAL 700 1- Manousopoulou A. aut SERVAL 700 1- Makrythanasis P. aut SERVAL 700 1- Saeed S. aut SERVAL 700 1- Falconnet E. aut SERVAL 700 1- Guipponi M. aut SERVAL 700 1- Pournaras C.J. aut SERVAL 700 1- Ansari M.A. aut SERVAL 700 1- Ranza E. aut SERVAL 700 1- Santoni F.A. aut SERVAL 700 1- Ahmed J. aut SERVAL 700 1- Shah I. aut SERVAL 700 1- Gul K. aut SERVAL 700 1- Black G.C. aut SERVAL 700 1- Bellen H.J. aut SERVAL 700 1- Antonarakis S.E. aut SERVAL 773 0- American journal of human genetics 103/4(2018-10-04), 568-578 103:4<568-578 2018 103 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article