Ansar, M., Chung, H.L., Taylor, R.L., Nazir, A., Imtiaz, S., Sarwar, M.T., Manousopoulou, A., Makrythanasis, P., Saeed, S., Falconnet, E., Guipponi, M., Pournaras, C.J., Ansari, M.A., Ranza, E., Santoni, F.A., Ahmed, J., Shah, I., Gul, K., Black, G.C., Bellen, H.J., Antonarakis, S.E. (2018). Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts.  Am. J. Hum. Genet. 103(4): 568--578.

FBrf0240231

Research paper

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.

PMC6174361 (PMC) (EuropePMC)