title: POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations.
abstract: Dystroglycan is a transmembrane glycoprotein whose interactions with the extracellular matrix (ECM) are necessary for normal muscle and brain development, and disruptions of its function lead to dystroglycanopathies, a group of congenital muscular dystrophies showing extreme genetic and clinical heterogeneity. Specific glycans bound to the extracellular portion of dystroglycan, α-dystroglycan, mediate ECM interactions and most known dystroglycanopathy genes encode glycosyltransferases involved in glycan synthesis. POMK, which was found mutated in two dystroglycanopathy cases, is instead involved in a glycan phosphorylation reaction critical for ECM binding, but little is known about the clinical presentation of POMK mutations or of the function of this protein in the muscle. Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects. We explored POMK expression in fetal and adult human muscle and identified widespread expression primarily during fetal development in myocytes and interstitial cells suggesting a role for this protein during early muscle differentiation. Analysis of loss of function in the zebrafish embryo and larva showed that pomk function is necessary for normal muscle development, leading to locomotor dysfuction in the embryo and signs of muscular dystrophy in the larva. In summary, we defined diverse clinical presentations following POMK mutations and showed that this gene is necessary for early muscle development.
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Costanzo
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Balasubramanian
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Pond
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Anete
authors.initials: A
authors.lastname: Rozkalne
authors.affiliation: Division of Neuromuscular Disease and Neuroimmunology, Fondazione di Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta, 20126 Milan, Italy and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
authors.affiliation: Division of Neuromuscular Disease and Neuroimmunology, Fondazione di Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta, 20126 Milan, Italy and.
authors.forename: Simona
authors.initials: S
authors.lastname: Saredi
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Vandana A
authors.initials: VA
authors.lastname: Gupta
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sunu
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Department of Neurology.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Division of Neuromuscular Disease and Neuroimmunology, Fondazione di Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta, 20126 Milan, Italy and.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Gussoni
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA, cmanzini@gwu.edu christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA, cmanzini@gwu.edu christopher.walsh@childrens.harvard.edu.
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000378:metabolism; D059472:Exome; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006031:Glycosylation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics*; D009154:Mutation; D009468:Neuromuscular Diseases / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D055815:Young Adult; D015027:Zebrafish
chemical_list: D049030:Dystroglycans; C583116:POMK protein, human; D011494:Protein Kinases