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

作者：Zhidong Cen, You Chen, Si Chen, Hong Wang, Dehao Yang, Hongmei Zhang, Hongwei Wu, Lebo Wang, Siyang Tang, Jia Ye, Jian Shen, Haotian Wang, Feng Fu, Xinhui Chen, Fei Xie, Peng Liu, Xuan Xu, Jianzhi Cao, Pan Cai, Qinqing Pan, Jieying Li, Wei Yang, Peng‐Fei Shan, Yuezhou Li, Jingyu Liu, Baorong Zhang, Wei Luo · 发表于：Brain · 年份：2019 · DOI：10.1093/brain/awz392 · 被引用次数：94 · 研究领域：Medical Imaging and Pathology Studies、Parathyroid Disorders and Treatments、Thyroid and Parathyroid Surgery

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the co...