PHACTR1 is associated with disease progression in Chinese Moyamoya disease

Area of Science:

• Genetics
• Neurology
• Vascular Biology

Background:

• Moyamoya disease (MMD) is a progressive stenosis of the internal carotid artery's terminal portion, predominantly affecting East Asian populations.
• The precise etiology of MMD remains largely unknown, necessitating further genetic and molecular investigations.
• Current diagnostic methods rely on digital subtraction angiography (DSA) for clinical confirmation.

Purpose of the Study:

• To identify genetic mutations predisposing to sporadic Moyamoya disease in Chinese patients.
• To investigate the association between specific genetic variants and disease progression in MMD.
• To elucidate the functional role of PHACTR1 in endothelial cell survival.

Main Methods:

• Whole-exome sequencing was performed on 31 sporadic MMD patients and 10 age- and gender-matched controls.
• Digital subtraction angiography (DSA) confirmed MMD diagnosis.
• Sanger sequencing validated specific single nucleotide variants (SNVs), and PHACTR1 gene expression was manipulated using siRNA in human coronary artery endothelial cells (HCAECs).

Main Results:

• Twelve predisposing mutations in seven genes (CCER2, HLA-DRB1, NSD-1, PDGFRB, PHACTR1, POGLUT1, RNF213) were identified in Chinese MMD patients.
• Eight deleterious SNVs (CADD PHRED score > 15) were found.
• A specific SNV in PHACTR1 (c.13185159G>T, p.V265L) was strongly associated with MMD progression.
• PHACTR1 knockdown reduced HCAEC survival under serum starvation conditions.

Conclusions:

• Novel predisposing mutations associated with Moyamoya disease have been identified.
• A specific PHACTR1 variant is linked to MMD disease progression.
• PHACTR1 plays a crucial role in endothelial cell survival, suggesting its involvement in MMD pathogenesis.