Biallelic COLGALT1 variants are associated with cerebral small vessel disease

Abstract

Objective

Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2‐related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20%–30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2‐related disorders.

Methods

Whole exome sequencing was performed in two families with suspected COL4A1/COL4A2‐related disorders. We validated the role of COLGALT1 variants by constructing a 3D structural model, evaluating ColGalT1 protein expression and ColGalT activity by western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments.

Results

Exome sequencing demonstrated biallelic variants in COLGALT1 encoding collagen β (1‐O) galactosyltransferase 1, which was involved in the post‐translational modification of type IV collagen in two unrelated patients: c.452T>G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G>C (p.Ala154Pro) and c.1129G>C (p.Gly377Arg) in Patient 2. 3D model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild‐type.

Interpretation

Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2‐related disorders.

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