Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Pontocerebellar hypoplasia (PCH) can involve supratentorial phenotypes and microcephaly.
• X-linked CASK gene mutations cause microcephaly with PCH in females, often lethal in males.
• CASK deficiency leads to cerebellar granule cell degeneration, with its broader brain role unclear.

Purpose of the Study:

• To investigate the function of CASK in the brain, particularly its role beyond the cerebellum.
• To explore the impact of CASK mutations and alternative splicing on its structure and function.

Main Methods:

• Generated conditional CASK knockout mice with postnatal deletion.
• Examined clinical features of individuals with CASK mutations.
• Performed phylogenetic and RT-PCR analyses of CASK splicing.
• Conducted in silico structural analysis of CASK.

Main Results:

• Postnatal CASK deletion in mice caused cerebellar degeneration and ataxia.
• Hemizygous CASK mutations in boys led to microcephaly and cerebral dysfunction without PCH.
• Vertebrate-specific CASK exons undergo alternative splicing, affecting the C-terminus structure and function.

Conclusions:

• CASK loss disproportionately affects the cerebellum.
• Clinical data suggest CASK has vertebrate-specific functions in the mammalian forebrain.
• CASK possesses both ancient conserved and novel vertebrate-specific functions.