Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

  • Ann Neurol. 2021 Aug;90(2):274-284. doi: 10.1002/ana.26147.
Egidio Spinelli  #  1 ,  Kyle R Christensen  #  2 ,  Emily Bryant  3  4 ,  Amy Schneider  5 ,  Jennifer Rakotomamonjy  6 ,  Alison M Muir  7 ,  Jessica Giannelli  3 ,  Rebecca O Littlejohn  8  9 ,  Elizabeth R Roeder  8  9 ,  Berkley Schmidt  10 ,  William G Wilson  10 ,  Elysa J Marco  11  12 ,  Kazuhiro Iwama  13 ,  Satoko Kumada  14 ,  Tiziana Pisano  15 ,  Carmen Barba  15 ,  Annalisa Vetro  15 ,  Eva H Brilstra  16 ,  Richard H van Jaarsveld  16 ,  Naomichi Matsumoto  13 ,  Hadassa Goldberg-Stern  17 ,  Patrick W Carney  18 ,  P Ian Andrews  19 ,  Christelle M El Achkar  17 ,  Sam Berkovic  5 ,  Lance H Rodan  20 ,  Undiagnosed Diseases Network (UDN) ,  Kirsty McWalter  21 ,  Renzo Guerrini  15 ,  Ingrid E Scheffer  5 ,  Heather C Mefford  7 ,  Simone Mandelstam  22  23 ,  Linda Laux  3  24 ,  John J Millichap  3  24 ,  Alicia Guemez-Gamboa  6 ,  Angus C Nairn  2 ,  Gemma L Carvill  24  25  26
Affiliations
  • 1. Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • 2. Department of Psychiatry, Yale School of Medicine, Connecticut Mental Health Center, New Haven, CT.
  • 3. Epilepsy Center and Division of Neurology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • 4. Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • 5. Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia.
  • 6. Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • 7. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA.
  • 8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
  • 9. Department of Pediatrics, Baylor College of Medicine, San Antonio, TX.
  • 10. Division of Medical Genetics, University of Virginia, Charlottesville, VA.
  • 11. Department of Pediatrics, University of California, San Francisco, CA.
  • 12. Research Division, Cortica Healthcare, San Rafael, CA.
  • 13. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 14. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
  • 15. Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
  • 16. Genetics Department, University Medical Centre Utrecht, Utrecht, The Netherlands.
  • 17. Epilepsy Unit and EEG Lab, Schneider Medical Center, Petah Tikv, Israel.
  • 18. Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
  • 19. Department of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia.
  • 20. Department of Neurology and Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
  • 21. GeneDx, Gaithersburg, MD.
  • 22. Department of Pediatrics and Radiology, University of Melbourne, Melbourne, VIC, Australia.
  • 23. Department of Medical Imaging, Royal Children's Hospital of Melbourne, Melbourne, VIC, Australia.
  • 24. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • 25. Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • 26. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • # Contributed equally.
PMID: 34185323 DOI: 10.1002/ana.26147
Abstract

Objective: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with Neurological Disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.

Methods: Using exome Sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells.

Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA Sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally.

Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.