PCNT point mutations and familial intracranial aneurysms. (4th December 2018)

• Record Type: Journal Article
• Authors: Lorenzo-Betancor, Oswaldo; Blackburn, Patrick R.; Edwards, Emily; Vázquez-do-Campo, Rocío; Klee, Eric W.; Labbé, Catherine; Hodges, Kyndall; Glover, Patrick; Sigafoos, Ashley N.; Soto, Alexandra I.; Walton, Ronald L.; Doxsey, Stephen; Bober, Michael B.; Jennings, Sarah; Clark, Karl J.; Asmann, Yan; Miller, David; Freeman, William D.; Meschia, James; Ross, Owen A.
• Is Part Of: Neurology. Volume 91:Number 23(2018)
• Publication Date: 2018-12-04
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000006614
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Objective: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. Methods: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. Results: We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. Conclusion: The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model ( Pcnt −/− ) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.