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

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Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification.
Brain ( IF 14.5 ) Pub Date : 2019-12-18 , DOI: 10.1093/brain/awz392
Zhidong Cen _{1,

2} , You Chen _{1,

2} , Si Chen _{1,

2} , Hong Wang ₃ , Dehao Yang _{1,

2} , Hongmei Zhang ₄ , Hongwei Wu ₅ , Lebo Wang ₁ , Siyang Tang ₆ , Jia Ye ₆ , Jian Shen ₇ , Haotian Wang ₁ , Feng Fu ₈ , Xinhui Chen ₁ , Fei Xie ₉ , Peng Liu ₁ , Xuan Xu ₁₀ , Jianzhi Cao ₁₀ , Pan Cai ₁₁ , Qinqing Pan _{1,

12} , Jieying Li ₁₃ , Wei Yang ₁₄ , Peng-Fei Shan ₁₅ , Yuezhou Li ₆ , Jing-Yu Liu ₁₀ , Baorong Zhang ₁ , Wei Luo ₁

Affiliation

Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Neurology, Ningbo Fourth Hospital, Ningbo, Zhejiang, China.
Department of Neurology, Lishui People's Hospital, Lishui, Zhejiang, China.
Children's Hospital and Department of Biophysics, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Neurology, Zhuji People's Hospital of Zhejiang Province, Shaoxing, Zhejiang, China.
Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
Department of Neurology, Wuyi First People's Hospital, Jinhua, Zhejiang, China.
Department of Neurology, Guiyang Second People's Hospital, Guiyang, Guizhou, China.
Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

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 cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.

更新日期：2020-02-10

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