Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts

Muhammad Ansar, Hyung lok Chung, Rachel L. Taylor, Aamir Nazir, Samina Imtiaz, Muhammad T. Sarwar, Alkistis Manousopoulou, Periklis Makrythanasis, Sondas Saeed, Emilie Falconnet, Michel Guipponi, Constantin J. Pournaras, Maqsood A. Ansari, Emmanuelle Ranza, Federico A. Santoni, Jawad Ahmed, Inayat Shah, Khitab Gul, Graeme CM Black, Hugo J. BellenStylianos E. Antonarakis

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.Thr951Metfs41) 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.

Original languageEnglish (US)
Pages (from-to)568-578
Number of pages11
JournalAmerican Journal of Human Genetics
Volume103
Issue number4
DOIs
StatePublished - Oct 4 2018

Keywords

  • bristles
  • cataract
  • cornea
  • DNMBP
  • Drosophila
  • ERG
  • eye development
  • photoreceptors
  • pigment cells
  • still life

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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