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

Am J Hum Genet. 2018 Oct 4;103(4):568-578. doi: 10.1016/j.ajhg.2018.09.004.


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.

Keywords: DNMBP; Drosophila; ERG; bristles; cataract; cornea; eye development; photoreceptors; pigment cells; still life.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Animals
  • Cadherins / genetics
  • Cataract / genetics*
  • Child
  • Cytoskeletal Proteins / genetics*
  • Drosophila / genetics
  • Epithelial Cells / pathology
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Homozygote
  • Humans
  • Lod Score
  • Loss of Heterozygosity / genetics*
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Tight Junctions / pathology


  • Cadherins
  • Cytoskeletal Proteins
  • DNMBP protein, human