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Original research
Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein
  1. Paras A Patel1,
  2. Leslie E W LaConte1,2,
  3. Chen Liang1,
  4. Thomas Cecere3,
  5. Deepa Rajan4,
  6. Sarika Srivastava1,5,
  7. Konark Mukherjee1,5
  1. 1Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA
  2. 2Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
  3. 3Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, USA
  4. 4University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  5. 5Department of Genetics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
  1. Correspondence to Dr Konark Mukherjee, Genetics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; konark{at}


Background Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain.

Method We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK’s structure.

Result We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus.

Conclusion Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s.

  • Biological Evolution
  • Genetic Diseases, Inborn
  • Genetic Diseases, X-Linked
  • Genetics, Medical
  • Human Genetics

Data availability statement

Data are available upon reasonable request.

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  • PAP and LEWL contributed equally.

  • Contributors PAP, LEWL and KM conceptualised experiments. PP, LL, CL, TC and KM performed experiments. PP, LL, DR, SS and KM analysed the results and wrote the manuscript. KM is the guarantor.

  • Funding The work in part and KM is supported by National Eye Institute grant (R01EY033391), and SS is supported by the NIH National Institute of Neurological Disorders and Stroke grant (R01NS117698).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.