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 uncharacterised 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.
Zha, CongyaoFarah, Carole A.Holt, Richard J.Ceroni, Fabiola AlAbdi, LamaThuriot, FannyKhan, Arif OHelaby, RanaLévesque, SébastienAlkuraya, Fowzan SKraus, AlisonRagge, Nicola Sossin, Wayne S
Department of Biological and Medical Sciences
Year of publication: 2020Date of RADAR deposit: 2020-09-23
This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of recordCongyao Zha, Carole A Farah, Richard J Holt, Fabiola Ceroni, Lama AlAbdi, Fanny Thuriot, Arif O Khan, Rana Helaby, Sébastien Lévesque, Fowzan S Alkuraya, Alison Kraus, Nicola Ragge, Wayne S Sossin, Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits., Human Molecular Genetics, ddaa198, is available online at: https://doi.org/10.1093/hmg/ddaa198