Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits
| Autor: | Alison Kraus, Arif O. Khan, Fanny Thuriot, Fowzan S. Alkuraya, Fabiola Ceroni, Wayne S. Sossin, Nicola K. Ragge, Rana Helaby, Carole A. Farah, Sébastien Lévesque, Richard J. Holt, Congyao Zha, Lama Al-Abdi |
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| Přispěvatelé: | Zha C., Farah C.A., Holt R.J., Ceroni F., Al-Abdi L., Thuriot F., Khan A.O., Helaby R., Levesque S., Alkuraya F.S., Kraus A., Ragge N.K., Sossin W.S. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Deafness Biology Nervous System Malformations Compound heterozygosity Microphthalmia 03 medical and health sciences 0302 clinical medicine Genetics medicine developmental eye defects Animals Humans Genetic Predisposition to Disease Eye Abnormalities Molecular Biology Genetics (clinical) 030304 developmental biology Mice Knockout 0303 health sciences Coloboma Anophthalmia Calpain Heterozygote advantage General Medicine medicine.disease CAPN15 Phenotype eye diseases Pedigree microphthalmia Neurodevelopmental Disorders biology.protein coloboma Eye disorder Female General Article sense organs 030217 neurology & neurosurgery |
| Zdroj: | Hum Mol Genet |
| Popis: | Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway. |
| Databáze: | OpenAIRE |
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