Department of Neurology Agnes Ginges Center for Human Neurogenetics Hadassah Medical Center Jerusalem Israel.
The Institute for Medical Research Israel-Canada (IMRIC) the Hebrew University Jerusalem Israel.
Ann Clin Transl Neurol. 2018 Nov 15;6(1):106-113. doi: 10.1002/acn3.684. eCollection 2019 Jan.
To investigate the genetic basis of the recessive form of primary familial brain calcification and study pathways linking a novel gene with known dominant genes that cause the disease.
Whole exome sequencing and Sanger-based segregation analysis were used to identify possible disease causing mutations. Mutation pathogenicity was validated by structural protein modeling. Functional associations between the candidate gene, , and genes previously implicated in the disease were examined through phylogenetic profiling.
We studied nine affected individuals from two unrelated families of Middle Eastern origin. The median age of symptom onset was 29.5 years (range 21-57 years) and dysarthria was the most common presenting symptom. We identified in the gene, a homozygous c.1233delC mutation in one family and c.1060_1062delGAC mutation in another. The first mutation results in protein truncation and the second in deletion of a highly conserved aspartic acid that is likely to disrupt binding of the protein with its substrate. Phylogenetic profiling analysis of the MYORG protein sequence suggests co-evolution with a number of calcium channels as well as other proteins related to regulation of anion transmembrane transport (False Discovery Rate, FDR < 10) and with PDCD6IP, a protein interacting with PDGFR which is known to be involved in the disease.
mutations are linked to a recessive form of primary familial brain calcification. This association was recently described in patients of Chinese ancestry. We suggest the possibility that mutations lead to calcification in a PDGFR -related pathway.
研究原发性家族性脑钙化隐性形式的遗传基础，并研究将一种新基因与导致该疾病的已知显性基因联系起来的途径。
使用全外显子组测序和基于 Sanger 的分离分析来鉴定可能的致病突变。通过结构蛋白建模验证突变的致病性。通过系统发育分析研究候选基因 和先前与该疾病相关的基因之间的功能关联。
我们研究了来自两个中东血统无关家庭的 9 名受影响个体。症状发作的中位年龄为 29.5 岁（范围为 21-57 岁），构音障碍是最常见的首发症状。我们在 基因中发现了一个纯合的 c.1233delC 突变，在一个家庭中发现了 c.1060_1062delGAC 突变。第一个突变导致蛋白质截断，第二个突变导致高度保守的天冬氨酸缺失，这可能破坏蛋白质与其底物的结合。MYORG 蛋白序列的系统发育分析表明，它与许多钙通道以及与阴离子跨膜转运调节相关的其他蛋白（假发现率，FDR<10）以及与 PDGFR 相互作用的 PDCD6IP 共同进化，已知 PDGFR 参与该疾病。
突变与原发性家族性脑钙化的隐性形式有关。这种关联最近在华裔患者中被描述。我们提出了 突变可能导致 PDGFR 相关途径钙化的可能性。
