@article{0aad2ec7d2d44d64b7b2642d257e4fdb,
title = "Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts",
abstract = "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), frameshift deletion 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.",
keywords = "bristles, cataract, cornea, DNMBP, Drosophila, ERG, eye development, photoreceptors, pigment cells, still life",
author = "Muhammad Ansar and Chung, {Hyung lok} and Taylor, {Rachel L.} and Aamir Nazir and Samina Imtiaz and Sarwar, {Muhammad T.} and Alkistis Manousopoulou and Periklis Makrythanasis and Sondas Saeed and Emilie Falconnet and Michel Guipponi and Pournaras, {Constantin J.} and Ansari, {Maqsood A.} and Emmanuelle Ranza and Santoni, {Federico A.} and Jawad Ahmed and Inayat Shah and Khitab Gul and Black, {Graeme CM} and Bellen, {Hugo J.} and Antonarakis, {Stylianos E.}",
note = "Funding Information: We thank the Swiss Government Excellence Scholarships program, which provided M.A. the opportunity to work at the University of Geneva Medical School in Switzerland. R.L.T is supported by the Medical Research Council through a UK Research and Innovation Fellowship (MR/R024952/1). We thank the Pro Visu Foundation for the grant support to S.E.A. This project was partially supported by European Research Council grant 219968 to S.E.A. H.J.B. is supported by the NIH (R24OD022005) and is an investigator of the Howard Hughes Medical Institute. The work conducted at Manchester Centre for Genomic Medicine (G.C.B and R.L.T) was supported by Fight for Sight UK (grant 1831). Confocal microscopy was performed in the neurovisualization core of the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (supported by National Institute of Child Health and Human Development [NICHD] grant U54HD083092). Drosophila stocks were obtained from the Bloomington Stock Center (NIH P40OD018537) at Indiana University. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD and maintained at the University of Iowa. We are thankful to all the members of the families reported in this study. Funding Information: We thank the Swiss Government Excellence Scholarships program, which provided M.A. the opportunity to work at the University of Geneva Medical School in Switzerland. R.L.T is supported by the Medical Research Council through a UK Research and Innovation Fellowship ( MR/R024952/1 ). We thank the Pro Visu Foundation for the grant support to S.E.A. This project was partially supported by European Research Council grant 219968 to S.E.A. H.J.B. is supported by the NIH ( R24OD022005 ) and is an investigator of the Howard Hughes Medical Institute. The work conducted at Manchester Centre for Genomic Medicine (G.C.B and R.L.T) was supported by Fight for Sight UK (grant 1831 ). Confocal microscopy was performed in the neurovisualization core of the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (supported by National Institute of Child Health and Human Development [NICHD] grant U54HD083092 ). Drosophila stocks were obtained from the Bloomington Stock Center ( NIH P40OD018537 ) at Indiana University. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD and maintained at the University of Iowa. We are thankful to all the members of the families reported in this study. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = oct,
day = "4",
doi = "10.1016/j.ajhg.2018.09.004",
language = "English (US)",
volume = "103",
pages = "568--578",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}