Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism
Simran Samra,
Mehul Sharma,
Maryam Vaseghi-Shanjani,
Kate L. Del Bel,
Loryn Byres,
Susan Lin,
Joshua Dalmann,
Areesha Salman,
Jill Mwenifumbo,
Bhavi P. Modi,
Catherine M. Biggs,
Cyrus Boelman,
Lorne A. Clarke,
Anna Lehman,
Stuart E. Turvey
Affiliations
Simran Samra
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada; Experimental Medicine Program, Department of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada
Mehul Sharma
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Maryam Vaseghi-Shanjani
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada; Experimental Medicine Program, Department of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada
Kate L. Del Bel
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Loryn Byres
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Susan Lin
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Joshua Dalmann
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Areesha Salman
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Jill Mwenifumbo
Department of Medical Genetics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Bhavi P. Modi
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Catherine M. Biggs
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Cyrus Boelman
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Lorne A. Clarke
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Anna Lehman
Department of Medical Genetics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada
Stuart E. Turvey
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, BC V6H 3N1, Canada; Corresponding author
Summary: Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mammalian target of rapamycin (mTOR) pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders. Here, we report a gain-of-function variant in MARK4 in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features. The siblings carry a germline heterozygous missense MARK4 variant c.604T>C (p.Phe202Leu), located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. The MARK4 variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway. In this study, we link a germline monoallelic MARK4 variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.
