Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Primary familial brain calcification (PFBC) is a monogenic disorder.
• Known causative genes include SLC20A2, PDGFRB, PDGFB, XPR1 (autosomal dominant), and MYORG (autosomal recessive).
• Autosomal recessive PFBC presents more severe phenotypes, necessitating identification of additional causative genes.

Purpose of the Study:

• To identify novel causative genes for autosomal recessive primary familial brain calcification.
• To investigate the role of JAM2 in PFBC pathogenesis.

Main Methods:

• Homozygosity mapping and whole genome sequencing were employed.
• Genetic screening was performed on a cohort of 398 probands.
• Functional studies using cell transfection and western blotting were conducted.

Main Results:

• Novel mutations in the JAM2 gene (frameshift, start codon, compound heterozygous) were identified in four PFBC patients from three families.
• Patients exhibited parkinsonism, dysarthria, seizures, and severe brain calcifications.
• Functional studies indicated that JAM2 mutations impair protein localization and function, potentially affecting neurovascular unit integrity.

Conclusions:

• JAM2 is identified as a novel causative gene for primary familial brain calcification.
• Impaired JAM2 function and neurovascular unit integrity are implicated in PFBC pathogenesis.
• This finding expands the genetic landscape of PFBC and emphasizes the neurovascular unit's role.