PCNT point mutations and familial intracranial aneurysms

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Intracranial aneurysms (IAs) and subarachnoid hemorrhages (SAHs) are significant cerebrovascular diseases.
• The genetic underpinnings of IA/SAH remain incompletely understood, necessitating the identification of novel causative genes.

Purpose of the Study:

• To identify novel genes implicated in the etiology of intracranial aneurysms (IAs) and subarachnoid hemorrhages (SAHs).
• To investigate the role of the PCNT gene in the pathogenesis of IA/SAH.

Main Methods:

• Whole-exome sequencing was performed on 13 individuals from 3 families with autosomal dominant IA/SAH.
• PCNT exon 38 was sequenced in an additional 161 idiopathic IA/SAH patients.
• Sanger sequencing was used to validate identified variants.

Main Results:

• Two distinct variants in the PCNT gene (p.R2728C and p.V2811L) were identified in affected individuals from two families.
• Five additional missense mutations in PCNT exon 38 were found in IA/SAH patients.
• A second carrier of the p.V2811L variant was identified in a family with a history of neurovascular diseases.

Conclusions:

• The PCNT gene, encoding a protein crucial for microtubule organization, is a highly plausible candidate gene for cerebrovascular diseases.
• Pathogenic variants in PCNT are associated with neurovascular abnormalities, including IAs and SAHs.
• The identified variants are located in a conserved protein-protein interaction domain, supporting their role in disease pathogenesis.