PCNT point mutations and familial intracranial Aneurysms
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.
Digital Object Identifier (DOI)
Lorenzo-Betancor, O., Blackburn, P. R., Edwards, E., Vázquez-do-Campo, R., Klee, E. W., Labbé, C., Hodges, K., Glover, P., Sigafoos, A. N., Soto, A. I., Walton, R. L., Doxsey, S., Bober, M. B., Jennings, S., Clark, K. J., Asmann, Y., Miller, D., Freeman, W. D., Meschia, J., & Ross, O. A. (2018). PCNT point mutations and familial intracranial aneurysms. Neurology, 91(23), e2170–e2181. https://doi.org/10.1212/WNL.0000000000006614