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.
- 1. Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
- 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
- 3. Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St. Mary's Hospital, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9PL, UK.
- 4. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan.
- 5. Department of Genetics, University of Karachi, Karachi 75270, Pakistan.
- 6. Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece.
- 7. Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland.
- 8. Hirslanden Clinique La Colline, Geneva 1206, Switzerland.
- 9. Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Department of Endocrinology Diabetes and Metabolism, University hospital of Lausanne, Lausanne 1011, Switzerland.
- 10. Department of Genetics, University of Karachi, Karachi 75270, Pakistan; Department of Bio Sciences, Faculty of Life Science, Mohammad Ali Jinnah University, Karachi 75400, Pakistan.
- 11. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston TX 77030, USA; Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
- 12. Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland. Electronic address: [email protected].
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.