原发性家族性脑钙化新致病基因的鉴定及功能研究

Primary familial brain calcification is one kind of neurological inherited disease radiologically characterized by bilateral brain calcifications and clinically characterized by an insidious and progressive development of movement disorders, cognitive decline, and psychiatric symptoms. To date, there were four autosomal dominant inherited causative genes - SLC20A2, PDGFRB, PDGFB and XPR1 identified, which improved our understanding to the pathogenesis of this disease. However, there were still some pedigrees whose causative genes were unknown. Recently we collected 10 consanguineous pedigrees with primary familial brain calcification. There are several affected siblings in 5 pedigrees and these parents’ CT scan showed no brain calcification. These clues indicate that there are autosomal recessive inherited causative genes existed in these pedigrees. We have found a probable causative gene - X gene in Pedigree A by using homozygosity mapping and whole-genome sequencing. We are trying to sequence X gene in other pedigrees and patients. Functional studies of X gene are also going to be done. In the following steps, we plan to identify the causative genes of other pedigrees. Further functional studies of X gene and other newly identified causative genes may help us to know further pathogenesis of primary familial brain calcification. This will contribute to the prevention, diagnosis and treatment of primary familial brain calcification.

原发性家族性脑钙化是一组以双侧对称性脑钙化为影像学特征，伴多种神经、精神症状的神经系统遗传性疾病。现共有4个致病基因SLC20A2、PDGFRB、PDGFB和XPR1被鉴定，均为常染色体显性遗传致病，仍有不少该病家系的致病基因尚不明确。本团队前期收集到10个十分罕见的患者父母近亲婚配的原发性家族性脑钙化家系，其中5个家系内有兄弟姐妹多人患病，父母头颅CT未见脑钙化，提示存在常染色体隐性遗传的新致病基因。前期通过纯合子定位及全基因组测序，我们在家系A中发现1个很可能的新致病基因X基因（文章尚未发表，基因名以X替代），目前正在其他家系及患者中进行验证，并拟通过建立疾病细胞模型和动物模型对其进行进一步的功能研究。下一步我们将结合纯合子定位、全基因组测序等技术鉴定其他家系的致病基因，同时对X基因及可能新发现的其他致病基因进行相关功能研究，进一步揭示该病的发病机制，为该病的防治及药物研发打下基础。

本项目到目前为止共收集了584个原发性家族性脑钙化（primary familial brain calcification，PFBC）家系先证者或散发患者，采集了患者及其家系成员的DNA样本及详细的临床资料。在项目研究计划和研究内容的引导下，顺利完成了相关研究目标，主要如下：1）在一个非常罕见的父母近亲结婚的PFBC家系中，应用纯合子定位、全基因组测序、Sanger测序大样本筛查，鉴定了一个新的致病基因JAM2；2）对收集的PFBC家系先证者或散发患者进行大样本的PFBC致病基因突变筛查，发现新突变和新表型，并估算了中国人群中PFBC的最小患病率；3）在PFBC家系发现MYORG的新突变和新表型，为鉴定MYORG基因为首个常染色体隐性遗传的PFBC致病基因提供了独立中心验证，进一步在大样本筛查中首次发现MYORG基因的杂合突变也可以引起脑钙化，其影像学外显率达到73.7%，该研究首次提供证据表明MYORG基因可能是一个PFBC常染色体显性遗传模式的基因，提示了PFBC的遗传异质性；4）成功构建了Jam2基因敲除小鼠模型，成功模拟出了JAM2基因突变患者的脑钙化表型，为进一步探索PFBC新致病基因JAM2的致病机制及开发药物靶点提供了重要的研究模型。在本项目资助下发表PFBC相关SCI论文4篇，其中1篇论文发表于神经科学顶级期刊Brain，2篇论文发表于运动障碍疾病顶级期刊Movement Disorders，1篇发表于运动障碍疾病权威期刊Parkinsonism & Related Disorders。另有6篇SCI论文受到该项目的资助，发表于Movement Disorders、Parkinsonism & Related Disorders等SCI期刊。