Dataset Information

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 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.

SUBMITTER: Zha C

PROVIDER: S-EPMC7645705 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Zha Congyao C Farah Carole A CA Holt Richard J RJ Ceroni Fabiola F Al-Abdi Lama L Thuriot Fanny F Khan Arif O AO Helaby Rana R Lévesque Sébastien S Alkuraya Fowzan S FS Kraus Alison A Ragge Nicola K NK Sossin Wayne S WS

Human molecular genetics 20201101 18

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 ...[more]

PMID: 32885237

Similar Datasets

Project description:Giant squids (Architeuthis) are a legendary species among the cephalopods. They live in the deep sea and are well known for their enormous body and giant eyes. It has been suggested that their giant eyes are not adapted for the detection of either mates or prey at distance, but rather are best suited for monitoring very large predators, such as sperm whales, at distances exceeding 120 m and at a depth below 600 m (Nilsson et al. 2012 Curr. Biol.22, 683-688. (doi:10.1016/j.cub.2012.02.031)). However, it is not clear how the brain of giant squids processes visual information. In this study, the optic lobe of a giant squid (Architeuthis dux, male, mantle length 89 cm), which was caught by local fishermen off the northeastern coast of Taiwan, was scanned using high-resolution magnetic resonance imaging in order to examine its internal structure. It was evident that the volume ratio of the optic lobe to the eye in the giant squid is much smaller than that in the oval squid (Sepioteuthis lessoniana) and the cuttlefish (Sepia pharaonis). Furthermore, the cell density in the cortex of the optic lobe is significantly higher in the giant squid than in oval squids and cuttlefish, with the relative thickness of the cortex being much larger in Architeuthis optic lobe than in cuttlefish. This indicates that the relative size of the medulla of the optic lobe in the giant squid is disproportionally smaller compared with these two cephalopod species. This morphological study of the giant squid brain, though limited only to the optic lobe, provides the first evidence to support that the optic lobe cortex, the visual information processing area in cephalopods, is well developed in the giant squid. In comparison, the optic lobe medulla, the visuomotor integration centre in cephalopods, is much less developed in the giant squid than other species. This finding suggests that, despite the giant eye and a full-fledged cortex within the optic lobe, the brain of giant squids has not evolved proportionally in terms of performing complex tasks compared with shallow-water cephalopod species.

Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets