학술논문
An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.
Document Type
Academic Journal
Author
Aloui C; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Neumann L; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Bergametti F; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Sartori E; Service de Neurologie, Centre Hospitalier Bretagne Sud, Lorient, France.; Herbreteau M; Service de Neurologie, Centre Hospitalier Bretagne Sud, Lorient, France.; Maillard A; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.; Coste T; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.; Morel H; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.; Hervé D; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Neurologie, Hôpital Lariboisière, Paris, France.; Chabriat H; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Neurologie, Hôpital Lariboisière, Paris, France.; Timsit S; Service de Neurologie Vasculaire, Centre Hospitalier Régional Universitaire de Brest, Brest, France.; Viakhireva I; Service de Neurologie Vasculaire, Centre Hospitalier Régional Universitaire de Brest, Brest, France.; Denoyer Y; Service de Neurologie, Centre Hospitalier Bretagne Sud, Lorient, France.; Université de Rennes, Laboratoire Traitement du Signal et de l'Image, Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche 1099, Rennes, France.; Allibert R; Service de Neurologie, Unité Neurovasculaire, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France.; Demurger F; Service de Neurologie, Unité Neurovasculaire, Centre Hospitalier Bretagne Atlantique, Vannes, France.; Gollion C; Service de Neurologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.; Vermersch P; Univ. Lille, Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche 1172 LilNCog, Centre Hospitalier Universitaire Lille, Fédérations Hospitalo-Universitaire Precise, Lille, France.; Marchelli F; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.; Blugeon C; GenomiqueENS, Institut de Biologie de l'Ecole Normale Supérieur, Département de biologie, École Normale Supérieure, Centre National de la Recherche Scientifique, Institut National de la Santé Et de la Recherche Médicale, Université Paris Sciences et Lettres, Paris, France.; Lemoine S; GenomiqueENS, Institut de Biologie de l'Ecole Normale Supérieur, Département de biologie, École Normale Supérieure, Centre National de la Recherche Scientifique, Institut National de la Santé Et de la Recherche Médicale, Université Paris Sciences et Lettres, Paris, France.; Tourtier-Bellosta C; Service de Neurologie, Centre Hospitalier Bretagne Sud, Lorient, France.; Brouazin A; Service de neurologie, Centre Hospitalier de Cornouaille, Quimper, France.; Leutenegger AL; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Pipiras E; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpitaux Jean Verdier et Armand Trousseau, Université Sorbonne Paris Nord, Bobigny, France.; Tournier-Lasserve E; NeuroDiderot, Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1141, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101729235 Publication Model: Electronic Cited Medium: Internet ISSN: 2574-3805 (Electronic) Linking ISSN: 25743805 NLM ISO Abbreviation: JAMA Netw Open Subsets: MEDLINE
Subject
Language
English
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.
Objective: To identify novel genes and mechanisms associated with familial CSVD.
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
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%]).
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.
Objective: To identify novel genes and mechanisms associated with familial CSVD.
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
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%]).
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.