Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction.

ABSTRACT: Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASK^M519T is incapable of bindin

SUBMITTER: LaConte LEW 

PROVIDER: S-EPMC6391276 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature