Primary familial brain calcification (PFBC), characterized by bilateral pathological calcium deposits in the basal ganglia and other brain regions, has grabbed the attention of researchers in recent years. Since the finding of SLC20A2, the first PFBC-associated gene, by Prof. LIU Jingyu at Huazhong University of Science and Technology in 2012, three other genes including PDGFRB, PDGFB and XPR1 have been found to be associated with PFBC.

In a recent study published in Neuron, a new causative factor for PFBC, mutation of MYORG gene, was demonstrated by Dr. XIONG Zhiqi’s lab at Institute of Neuroscience (ION), CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences (CAS), and Prof. CHEN Wanjin and Prof. WANG Ning’s group at The First Affiliated Hospital of Fujian Medical University (FMU). 

Mutations in MYORG gene, also known as KIAA1161 or NET37, locates at 9p133 and encodes a protein product with 714 amino acids that belong to glycosidase subfamiliy 31. This study identified the loss of function mutation in MYORG gene as a new genetic cause of PFBC in a recessive pattern, and this association was confirmed by the development of calcification deposition in the brain of Myorg homozygous knockout mice.

Over the past years, researchers from FMU collected dozens of PFBC families that distributed all over the country. Using whole exosome sequencing and Sanger sequencing, they found six PFBC families co-segregated with mutations in MYORG gene.

Collaborating with them, researchers at ION found a selective expression of Myorg gene in S100b-positive astrocyte by in situ hybridization, and the complete overlap expression of GFP that knocked-in after endogenous Myorg promoter with S100b-positive astrocyte reconfirmed this specific expression pattern.

They revealed that the development of calcification deposits in brains of mice at an age over eight months has a similar element composition as that of human patients, suggesting that loss-of-function of Myorg is a causative factor of brain calcification.

MYORG was identified as the first autosomal recessive gene for PFBC, and mutation of this gene accounts for 11% of total PFBC families and 50% of recessive families, suggesting MYORG mutation a critical genetic factor of PFBC.

The selective expression of MYORG in astrocytes demonstrated that astrocyte is a new cell type involved in brain calcification. Astrocytes are also an essential component of the blood-brain barrier both in human and rodent brains besides pericytes, in which deficiency of PDGFB-PDGFRB signaling causes brain calcification. This finding established a new keystone for the cellular pathological theory of brain calcification.

Brain calcification has aging-associated prevalence more than 20% in the elderly. Patients with bulk brain calcification usually present progressive movement disorders (dystonia, ataxia, parkinsonism, chorea), neuropsychiatric symptoms and cognitive dysfunction. The genetic causes of over 50% families of PFBC remains unidentified.