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An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Authors :
Aloui C
Neumann L
Bergametti F
Sartori E
Herbreteau M
Maillard A
Coste T
Morel H
Hervé D
Chabriat H
Timsit S
Viakhireva I
Denoyer Y
Allibert R
Demurger F
Gollion C
Vermersch P
Marchelli F
Blugeon C
Lemoine S
Tourtier-Bellosta C
Brouazin A
Leutenegger AL
Pipiras E
Tournier-Lasserve E
Source :
JAMA network open [JAMA Netw Open] 2024 Apr 01; Vol. 7 (4), pp. e247034. Date of Electronic Publication: 2024 Apr 01.
Publication Year :
2024

Abstract

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.<br />Objective: To identify novel genes and mechanisms associated with familial CSVD.<br />Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset <age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group.<br />Main Outcomes and Measures: A pathogenic AluYa5 insertion was identified within the COL4A1 3'UTR in the 2 large families with CSVD. Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed.<br />Results: Among 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10-4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10-12). In these 7 patients' families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]).<br />Conclusions and Relevance: This study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications.

Details

Language :
English
ISSN :
2574-3805
Volume :
7
Issue :
4
Database :
MEDLINE
Journal :
JAMA network open
Publication Type :
Academic Journal
Accession number :
38630472
Full Text :
https://doi.org/10.1001/jamanetworkopen.2024.7034