Autosomal dominant stromal corneal dystrophy associated with a SPARCL1 missense variant

Braddock, Freddie L., Gardner, Jessica C., Bhattacharyya, Nihar, Sanchez-Pintado, Beatriz, Costa, Marcos, Zarouchlioti, Christina, Szabo, Anita, Lišková, Petra, Cheetham, Michael E., Young, Robert D. ORCID: https://orcid.org/0000-0002-8300-8002, Thaung, Caroline, Davidson, Alice E., Tuft, Stephen J. and Hardcastle, Alison J. 2024. Autosomal dominant stromal corneal dystrophy associated with a SPARCL1 missense variant. European Journal of Human Genetics 32 (12) , pp. 1583-1589. 10.1038/s41431-024-01687-8

	PDF - Published Version Download (2MB)
	PDF - Supplemental Material Download (443kB)

Abstract

Corneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1, NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1, extending the phenotypic and genetic heterogeneity of inherited corneal disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Optometry and Vision Sciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	1018-4813
Date of First Compliant Deposit:	2 December 2024
Date of Acceptance:	14 August 2024
Last Modified:	02 Dec 2024 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/174438

Actions (repository staff only)

Edit Item