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Hum Mol Genet. 2014 Nov 1;23(21):5781-92. doi: 10.1093/hmg/ddu296. Epub 2014 Jun 11.

POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations.

Author information

1
Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
2
Division of Genetics and Genomics and the Manton Center for Orphan Disease Research.
3
Division of Neuromuscular Disease and Neuroimmunology, Fondazione di Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta, 20126 Milan, Italy and.
4
Department of Neurology.
5
Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi Arabia.
6
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.
7
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.

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.

PMID:
24925318
PMCID:
PMC4189906
DOI:
10.1093/hmg/ddu296
[Indexed for MEDLINE]
Free PMC Article

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