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Original research
Complete loss of the X-linked gene CASK causes severe cerebellar degeneration
  1. Paras A Patel1,
  2. Julia V Hegert2,
  3. Ingrid Cristian3,
  4. Alicia Kerr1,
  5. Leslie E W LaConte1,
  6. Michael A Fox1,4,
  7. Sarika Srivastava1,5,
  8. Konark Mukherjee1,6
  1. 1 Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA
  2. 2 Department of Pathology, Orlando Health, Orlando, Florida, USA
  3. 3 Orlando Health, Orlando, Florida, USA
  4. 4 School of Neuroscience, Blacksburg, Virginia, USA
  5. 5 Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
  6. 6 Department of Psychiatry, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
  1. Correspondence to Dr Konark Mukherjee, Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA; konark{at}


Background Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration.

Method Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.

Result The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration.

Conclusion We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

  • paediatrics
  • pathology
  • nervous system diseases
  • congenital
  • hereditary
  • neonatal diseases and abnormalities
  • central nervous system diseases

Data availability statement

Data are available on reasonable request. Not applicable’.

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  • Contributors Experiments were conceived by KM, PP, MF and IC. Data analysed by KM, MF, PP, JH, LEWL and SS. Experiments conducted by PP, AK and JH. Paper written by KM, PP, MF, LEWL, SS, IC and JH. Guarantor: KM. All authors read and approved the final manuscript.

  • Funding The work was supported with funding from the NIH National Eye Institute (R01EY024712) and Angelina CASK Neurological Research Foundation to KM, and from the NIH National Institute of Neurological Disorders and Stroke grant (R01NS117698) to S.S.

  • 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.