Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts.
Am J Hum Genet
; 103(4): 568-578, 2018 10 04.
Article
en En
| MEDLINE
| ID: mdl-30290152
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 â¼50% 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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Variación Genética
/
Catarata
/
Pérdida de Heterocigocidad
/
Predisposición Genética a la Enfermedad
/
Proteínas del Citoesqueleto
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Animals
/
Child
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Año:
2018
Tipo del documento:
Article