Biallelic COLGALT1 variants are associated with cerebral small vessel disease

This study aimed to identify novel genes that causeCOL4A1/COL4A2‐related disorders.MethodsWhole exome sequencing was performed in two families with suspectedCOL4A1/COL4A2‐related disorders. We validated the role ofCOLGALT1 variants by constructing a 3D structural model, evaluating ColGalT1 protein expression and ColGalT activity by western blotting and collagen galactosyltransferase assays, and performingin vitro RNA interference and rescue experiments.ResultsExome sequencing demonstrated biallelic variants inCOLGALT1 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 mutantCOLGALT1 insufficiently restored COL4A1 production in cells compared with wild ‐type.InterpretationBiallelicCOLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis withCOL4A1/COL4A2‐related disorders.This article is protected by copyright. All rights reserved.

Source: Annals of Neurology - November 9, 2018 Category: Neurology Authors: Satoko Miyatake, Sacha Schneeberger, Norihisa Koyama, Kenji Yokochi, Kayo Ohmura, Masaaki Shiina, Harushi Mori, Eriko Koshimizu, Eri Imagawa, Yuri Uchiyama, Satomi Mitsuhashi, Martin C. Frith, Atsushi Fujita, Mai Satoh, Masataka Taguri, Yas Tags: Research Article Source Type: research