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Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy
Author(s) -
Spinelli Egidio,
Christensen Kyle R.,
Bryant Emily,
Schneider Amy,
Rakotomamonjy Jennifer,
Muir Alison M.,
Giannelli Jessica,
Littlejohn Rebecca O.,
Roeder Elizabeth R.,
Schmidt Berkley,
Wilson William G.,
Marco Elysa J.,
Iwama Kazuhiro,
Kumada Satoko,
Pisano Tiziana,
Barba Carmen,
Vetro Annalisa,
Brilstra Eva H.,
Jaarsveld Richard H.,
Matsumoto Naomichi,
GoldbergStern Hadassa,
Carney Patrick W.,
Andrews P. Ian,
El Achkar Christelle M.,
Berkovic Sam,
Rodan Lance H.,
McWalter Kirsty,
Guerrini Renzo,
Scheffer Ingrid E.,
Mefford Heather C.,
Mandelstam Simone,
Laux Linda,
Millichap John J.,
GuemezGamboa Alicia,
Nairn Angus C.,
Carvill Gemma L.
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26147
Subject(s) - missense mutation , epilepsy , biology , exome sequencing , hek 293 cells , gene , genetics , mutation , medicine , neuroscience
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