A Novel Loss-of-function Pathogenic Missense Mutation in CASK Gene Causes Mental Retardation and Microcephaly with Pontine and Cerebellar Hypoplasia

Abstract Background: Mutations in the CASK gene result in a wide range of observed phenotypes in humans like FG Syndrome 4 and mental retardation. In this study, researchers investigated the case of an 11-month-old female diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). These issues caused general developmental delays, microcephaly, and cerebellar hypoplasia. Results: Whole-exome sequencing (WES) was used to identify a novel pathogenic missense mutation (NM_003688.3: c.638T>G) in the CASK gene in this index. Researchers further confirmed the pathogenicity of the missense mutation by bioinformatics analysis. At the same time, researchers tested its protein expression level and mRNA expression level. Strikingly, the protein expression was down-regulation while the mRNA expression was not changed. By using protein structure prediction, this study found that amino acid mutation resulted in further changes in the stability of protein structures, which caused down-regulation of the protein expression and loss of the protein function. Conclusions: In this study, researchers first reported a novel causative mechanism of MICPCH: amino acid mutations led to changes in protein structure and down-regulation of stability, which caused protein was loss of function. This study can be helpful in the genetic diagnosis of this disease.