Biallelic COLGALT1 variants are associated with cerebral small vessel disease PMID: 30412317

GLP-1 and Obesity Research

2026-08-18

Biallelic COLGALT1 variants are associated with cerebral small vessel disease

Ann Neurol. 2018 Dec;84(6):843-853. doi: 10.1002/ana.25367.

Satoko Miyatake ¹ ² , Sacha Schneeberger ³ , Norihisa Koyama ⁴ , Kenji Yokochi ⁴ ⁵ , Kayo Ohmura ⁶ , Masaaki Shiina ⁷ , Harushi Mori ⁸ , Eriko Koshimizu ¹ , Eri Imagawa ¹ , Yuri Uchiyama ¹ , Satomi Mitsuhashi ¹ , Martin C Frith ⁹ ¹⁰ ¹¹ , Atsushi Fujita ¹ , Mai Satoh ¹ , Masataka Taguri ¹² , Yasuko Tomono ¹³ , Keita Takahashi ¹⁴ , Hiroshi Doi ¹⁴ , Hideyuki Takeuchi ¹⁴ , Mitsuko Nakashima ¹ ¹⁵ , Takeshi Mizuguchi ¹ , Atsushi Takata ¹ , Noriko Miyake ¹ , Hirotomo Saitsu ¹ ¹⁵ , Fumiaki Tanaka ¹⁴ , Kazuhiro Ogata ⁷ , Thierry Hennet ³ , Naomichi Matsumoto ¹

Affiliations

1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
2. Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan.
3. Institute of Physiology, University of Zurich, Zurich, Switzerland.
4. Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Japan.
5. Department of Pediatrics, Seirei Mikatahara General Hospital, Shizuoka, Japan.
6. Department of Pediatric Neurology, Morinomiya Hospital, Osaka, Japan.
7. Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
8. Department of Radiology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
9. Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
10. Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
11. Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
12. Department of Data Science, Yokohama City University School of Data Science, Yokohama, Japan.
13. Division of Molecular and Cell Biology, Shigei Medical Research Institute, Okayama, Japan.
14. Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
15. Department of Biochemistry, Hamamatsu University School of Medicine, Shizuoka, Japan.

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 to 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 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating Collagen β (1-O) galactosyltransferase 1 (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 ColGalT1, which was involved in the post-translational modification of type IV Collagen in 2 unrelated patients: c.452 T > 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. Three-dimensional 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. Ann Neurol 2018;84:843-853.