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

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 ¼ 5.18 at q ¼ 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.

Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature

“…Developmental delay first became evident at the age of 5 months. Working memory was assessed by the Frontal Assessment Battery (31) and the Raven's Colored Progressive Matrices (32,33) for which the following scores were recorded: 8 (16.5) and 14.7 (19), respectively. Last, visuospatial processing was evaluated by the Rey's Complex Figure were reported by parents since the proband was a child, but neither polysomnography nor electroencephalograph recording was available to the investigators at the time of the present study.…”

“…Autosomal recessive disorders are common in populations where consanguineous marriages are frequent and consanguinity is considered as one of the major contributing factors of child morbidity and mortality (12)(13)(14)(15)(16)(17)(18). Studying consanguineous families with more than one affected offspring has proven to be an effective strategy to discover causative pathogenic variants in novel recessive genes and improve genetic diagnosis (15,19).…”

Identification and Profiling of MicroRNAs During Embryogenesis in the Red Claw Crayfish Cherax quadricarinatus

“…A target gene is turtle (tutl), which is involved in axonal targeting of the R7 photoreceptor in the developing eye (Cameron et al, 2013). The other two genes associated with eye development are the target gene of miR-50 and miR-1260b, miR-50 target gene fbx5 (F-box/WD repeat-containing protein 5) negatively regulates cell growth, and proliferation in the wing and eye during Drosophila development (Moberg et al, 2001), on the contrary, miR-1260b target gene sif (protein still life, isoforms C/SIF type 2) is required for eye development of Drosophila (Ansar et al, 2018). These three miRNAs were expressed in all three stages of study, which may co-regulate the eye development of C. quadricarinatus embryonic.…”

Congenital cataract: a guide to genetic and clinical management

“…Biallelic loss-of-function variants have been shown to result in autosomal recessive cataract with other ocular features, including pupil abnormalities, strabismus and nystagmus. 40 Transcription factors. Heat shock transcription factor 4 (HSF4) protects lens proteins from cell stressors and has a regulatory role in the differentiation of lens fibre cells.…”