PCNT point mutations and familial intracranial aneurysms

Oswaldo Lorenzo-Betancor, Patrick R. Blackburn, Emily Edwards, Rocío Vázquez-do-Campo, Eric W Klee, Catherine Labbé, Kyndall Hodges, Patrick Glover, Ashley N. Sigafoos, Alexandra I. Soto, Ronald L. Walton, Stephen Doxsey, Michael B. Bober, Sarah Jennings, Karl J Clark, Yan Asmann, David Miller, William D. Freeman, James F Meschia, Owen A Ross

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e2170-e2181
JournalNeurology
Volume91
Issue number23
DOIs
StatePublished - Dec 4 2018

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Intracranial Aneurysm
Subarachnoid Hemorrhage
Point Mutation
Intracranial Hemorrhages
Exome
Exons
Genes
Protein Interaction Domains and Motifs
Cerebrovascular Disorders
Dwarfism
Inheritance Patterns
Interphase
Missense Mutation
Mitosis
Knockout Mice
Microtubules
Blood Vessels
Organizations
Mutation
Proteins

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Lorenzo-Betancor, O., Blackburn, P. R., Edwards, E., Vázquez-do-Campo, R., Klee, E. W., Labbé, C., ... Ross, O. A. (2018). PCNT point mutations and familial intracranial aneurysms. Neurology, 91(23), e2170-e2181. https://doi.org/10.1212/WNL.0000000000006614

PCNT point mutations and familial intracranial aneurysms. / 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 F; Ross, Owen A.

In: Neurology, Vol. 91, No. 23, 04.12.2018, p. e2170-e2181.

Research output: Contribution to journalArticle

Lorenzo-Betancor, O, Blackburn, PR, Edwards, E, Vázquez-do-Campo, R, Klee, EW, Labbé, C, Hodges, K, Glover, P, Sigafoos, AN, Soto, AI, Walton, RL, Doxsey, S, Bober, MB, Jennings, S, Clark, KJ, Asmann, Y, Miller, D, Freeman, WD, Meschia, JF & Ross, OA 2018, 'PCNT point mutations and familial intracranial aneurysms', Neurology, vol. 91, no. 23, pp. e2170-e2181. https://doi.org/10.1212/WNL.0000000000006614
Lorenzo-Betancor O, Blackburn PR, Edwards E, Vázquez-do-Campo R, Klee EW, Labbé C et al. PCNT point mutations and familial intracranial aneurysms. Neurology. 2018 Dec 4;91(23):e2170-e2181. https://doi.org/10.1212/WNL.0000000000006614
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 F ; Ross, Owen A. / PCNT point mutations and familial intracranial aneurysms. In: Neurology. 2018 ; Vol. 91, No. 23. pp. e2170-e2181.
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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.",
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T1 - PCNT point mutations and familial intracranial aneurysms

AU - Lorenzo-Betancor, Oswaldo

AU - Blackburn, Patrick R.

AU - Edwards, Emily

AU - Vázquez-do-Campo, Rocío

AU - Klee, Eric W

AU - Labbé, Catherine

AU - Hodges, Kyndall

AU - Glover, Patrick

AU - Sigafoos, Ashley N.

AU - Soto, Alexandra I.

AU - Walton, Ronald L.

AU - Doxsey, Stephen

AU - Bober, Michael B.

AU - Jennings, Sarah

AU - Clark, Karl J

AU - Asmann, Yan

AU - Miller, David

AU - Freeman, William D.

AU - Meschia, James F

AU - Ross, Owen A

PY - 2018/12/4

Y1 - 2018/12/4

N2 - 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.

AB - 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.

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