Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits

Abstract

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.

Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay

“…In conclusion, our findings expand the phenotype previously reported by Zha et al (2020) 11 of CAPN15 pathogenic variants in humans. While missense variants were reported to cause mainly eye defects, we report the first case of a biallelic LOF variant associated with a severe neurodevelopmental disorder in two siblings.…”

“…Recently, CAPN15 , the only SOL calpain, was found to cause human eye defects, along with variable extra‐ocular findings (Table 1). This correlates with the high expression of CAPN15 in retinal ganglion cells 11 . All five individuals reported in the literature had biallelic predicted deleterious missense variants in CAPN15 .…”

“…Capn15 knockout (KO) mice showed variable eye defects (including cataract, coloboma, and microphthalmia), decreased viability, and smaller mean weight. The results suggested an essential role for CAPN15 in embryonic brain development 11 …”

“…It is ubiquitously expressed 1,2 (GTEx Portal, 10 Figure S1), with high expression in brain. Recently, Zha et al 11 demonstrated a role for pathogenic variants in CAPN15 in congenital cataract and microphthalmia in humans, with variable global developmental delay, growth deficits and hearing loss. Capn15 knockout (KO) mice showed variable eye defects (including cataract, coloboma, and microphthalmia), decreased viability, and smaller mean weight.…”

MRI ofCapn15knockout mice and analysis of Capn 15 distribution reveal possible roles in brain development and plasticity

“…We have recently generated Capn15 knockout (KO) mice and showed that loss of Capn15 leads to a lower Mendelian ratio, a smaller weight of weaned Capn15 KO mice and developmental eye anomalies (Zha et al, 2020). Human individuals with biallelic variants in CAPN15 also have developmental eye anomalies (Zha, et al, 2020), and a subset of these individuals have developmental delays and autism. However, how loss of Capn15 affects brain development and where Capn15 is expressed in the adult are not known.…”