MYORG is associated with recessive primary familial brain calcification

Area of Science:

• Neurogenetics
• Molecular Biology
• Biochemistry

Background:

• Primary familial brain calcification (PFBC) is a rare neurological disorder characterized by abnormal calcium deposition in the brain.
• While dominant forms are linked to known genes, the genetic basis of recessive PFBC remains less understood.
• Identifying novel genes and pathways is crucial for understanding PFBC pathogenesis.

Purpose of the Study:

• To investigate the genetic underpinnings of the recessive form of primary familial brain calcification.
• To explore potential molecular pathways connecting a newly identified gene with established dominant PFBC genes.

Main Methods:

• Whole exome sequencing and Sanger sequencing were employed to identify mutations in affected individuals from two Middle Eastern families.
• Structural protein modeling was used to assess the pathogenicity of identified mutations.
• Phylogenetic profiling was utilized to examine functional associations between the candidate gene, MYORG, and known disease-related genes.

Main Results:

• Homozygous mutations (c.1233delC and c.1060_1062delGAC) in the MYORG gene were identified in the studied families.
• These mutations lead to protein truncation or deletion of a conserved residue, likely impairing protein function.
• Phylogenetic analysis revealed co-evolution of MYORG with calcium channels and proteins involved in anion transport, and with PDCD6IP, a protein interacting with PDGFR beta.

Conclusions:

• MYORG mutations are associated with a recessive form of primary familial brain calcification, consistent with recent findings in Chinese populations.
• The study suggests that MYORG mutations may contribute to brain calcification through a pathway involving PDGFR beta.
• These findings expand the genetic landscape of PFBC and highlight potential shared molecular mechanisms.