Autosomal dominant stromal corneal dystrophy associated with a SPARCL1 missense variant.

Autor: Braddock FL; UCL Institute of Ophthalmology, University College London, London, UK., Gardner JC; UCL Institute of Ophthalmology, University College London, London, UK., Bhattacharyya N; UCL Institute of Ophthalmology, University College London, London, UK., Sanchez-Pintado B; UCL Institute of Ophthalmology, University College London, London, UK., Costa M; UCL Institute of Ophthalmology, University College London, London, UK., Zarouchlioti C; UCL Institute of Ophthalmology, University College London, London, UK., Szabo A; UCL Institute of Ophthalmology, University College London, London, UK., Lišková P; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic., Cheetham ME; UCL Institute of Ophthalmology, University College London, London, UK., Young RD; Structural Biophysics Group, School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK., Thaung C; UCL Institute of Ophthalmology, University College London, London, UK., Davidson AE; UCL Institute of Ophthalmology, University College London, London, UK., Tuft SJ; UCL Institute of Ophthalmology, University College London, London, UK.; Department of Corneal and External Eye Disease, Moorfields Eye Hospital, London, UK., Hardcastle AJ; UCL Institute of Ophthalmology, University College London, London, UK. a.hardcastle@ucl.ac.uk.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Dec; Vol. 32 (12), pp. 1583-1589. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41431-024-01687-8
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the Research Ethics Committees of University College London (UCL) (22/EE/0090) and Moorfields Eye Hospital (MEH) London (13/LO/1084) and was conducted in accordance/compliance with the Declaration of Helsinki. A written informed consent form was obtained from all participants who provided peripheral blood or corneal tissue samples. Control corneal tissue was similarly isolated from donor corneoscleral discs rejected for clinical transplantation (Miracles in Sight Eye Bank, TX, USA).
(© 2024. The Author(s).)
Databáze: MEDLINE
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