Joint Laboratory of Reproductive Medicine, Gynaecology and Paediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
West China School of Pharmacy, Sichuan University, Chengdu, 610041, People's Republic of China.
BMC Med Genomics. 2022 Jun 6;15(1):127. doi: 10.1186/s12920-022-01275-z.
Variants in the CASK gene result in a wide range of observed phenotypes in humans, such as FG Syndrome 4 and intellectual disabilities. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder that affects females and is characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Variants in CASK are the main genetic cause of MICPCH. Variants in CASK can explain most patients with MICPCH, but there are still some patients whose disease aetiology cannot be explained.
An 11-month-old female diagnosed with MICPCH exhibited general developmental delays, microcephaly, and cerebellar hypoplasia. Whole-exome sequencing (WES) was used to find a novel heterozygous missense variant (NM_003688.3: c.638T>G) of CASK in this patient. Strikingly, this variant reduced the expression of CASK at the protein level but not at the mRNA level. By using protein structure prediction analysis, this study found that the amino acid change caused by the variant resulted in further changes in the stability of the protein structure, and these changes caused the downregulation of protein expression and loss of protein function.
In this study, we first reported a novel heterozygous pathogenic variant and a causative mechanism of MICPCH. The amino acid change cause by this variant led to changes in the protein structure and a decrease in its stability, which caused a loss of protein function. This study could be helpful to the genetic diagnosis of this disease.
CASK 基因的变异导致人类出现广泛的表型，如 FG 综合征 4 型和智力障碍。伴有小头和桥脑小脑发育不良的 X 连锁智力发育障碍（MICPCH）是一种影响女性的 X 连锁疾病，其特征为严重的智力发育障碍和桥脑小脑发育不良的不同程度。CASK 中的变异是 MICPCH 的主要遗传原因。CASK 的变异可以解释大多数 MICPCH 患者，但仍有一些患者的疾病病因无法解释。
一名 11 个月大的女性被诊断为 MICPCH，表现为全面发育迟缓、小头和小脑发育不良。全外显子组测序（WES）在该患者中发现了 CASK 的一种新的杂合错义变异（NM_003688.3：c.638T>G）。引人注目的是，这种变异降低了 CASK 在蛋白质水平上的表达，但在 mRNA 水平上没有。通过使用蛋白质结构预测分析，本研究发现，该变异引起的氨基酸变化进一步导致了蛋白质结构稳定性的变化，这些变化导致了蛋白质表达的下调和蛋白质功能的丧失。
在这项研究中，我们首次报道了一种新的杂合致病性变异和 MICPCH 的致病机制。该变异引起的氨基酸变化导致了蛋白质结构的改变和稳定性的降低，从而导致了蛋白质功能的丧失。本研究可能有助于该疾病的遗传诊断。
