Department of Genetics, King Faisal Specialist Hospital, and Research Centre, PO Box 3354, Riyadh, 11211, Saudi Arabia.
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Hum Genomics. 2017 Nov 6;11(1):25. doi: 10.1186/s40246-017-0123-5.
Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants.
Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition.
Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.
从一个超过 24 年的有血缘关系的大家庭中，我们发现了 5 名患有震颤性肌张力障碍、痉挛和脑白质病的综合征患者。我们采用全基因组连锁、纯合性作图和全外显子测序的定位克隆方法对其进行了基因特征分析。使用荧光报告表达盒研究了钙调蛋白结合转录激活因子 2（CAMTA2）同种型 2 的低功能突变对 mRNA 和蛋白丰度的影响。利用人类脑亚区 cDNA 文库研究了 CAMTA2 转录变体的表达模式。
连锁分析和纯合性作图将疾病等位基因定位于染色体 17 上的 2.1 Mb 区间，LOD 得分为 4.58。全外显子组测序发现 CAMTA2 转录变体 2 的 5'UTR 中存在一个 G>A 变化，仅位于翻译起始位点上游 6 个碱基（c.-6G>A）（NM_001171166.1），并以常染色体隐性方式与疾病共分离。野生型和突变型 5'UTR 连接的荧光报告转染显示，mRNA 水平没有影响，但蛋白荧光活性显著降低，暗示翻译抑制。
CAMTA2 的突变导致其自身基因活性的转录后抑制，可能是一种新型震颤性肌张力障碍的基础。
