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

Rachel L Taylor, Graeme Black

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)568-578
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number4
Early online date4 Oct 2018
Publication statusPublished - 2018


  • infantile cataract
  • exome sequencine
  • loss-of-function
  • Still Life
  • sif
  • cataract
  • cornea
  • Drosophila
  • eye development
  • still life
  • photoreceptors
  • bristles
  • pigment cells
  • ERG
  • Loss of Heterozygosity/genetics
  • Humans
  • Middle Aged
  • Genetic Predisposition to Disease/genetics
  • Male
  • Genetic Variation/genetics
  • Lod Score
  • Drosophila/genetics
  • Tight Junctions/pathology
  • Adult
  • Exome/genetics
  • Female
  • Child
  • Cytoskeletal Proteins/genetics
  • Cadherins/genetics
  • Epithelial Cells/pathology
  • Homozygote
  • Phenotype
  • Animals
  • Cataract/genetics
  • Pedigree
  • Alleles


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