Identification of DPAGT1 as a new gene in which mutations cause a congenital myasthenic syndrome

Congenital myasthenic syndromes (CMS) are a group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. This is a heterogenous group of disorders with 15 different genes implicated in the development of the disease. Using whole‐exome sequencing we identified DPAGT1 as a new gene associated with CMS. DPAGT1 catalyses the first step of N‐linked protein glycosylation. DPAGT1 patients are characterized by weakness of limb muscles, response to treatment with cholinesterase inhibitors, and the presence of tubular aggregates on muscle biopsy. We showed that DPAGT1 is required for glycosylation of acetylcholine receptor (AChR) subunits and efficient export of AChR to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1‐associated CMS is reduced levels of AChRs at the endplate region. This finding demonstrates that impairment of the N‐linked glycosylation pathway can lead to the development of CMS.

[1]  J. Hofsteenge,et al.  Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. , 2009, American journal of human genetics.

[2]  K. Sumikawa,et al.  Site-directed mutagenesis of the conserved N-glycosylation site on the nicotinic acetylcholine receptor subunits. , 1991, Brain research. Molecular brain research.

[3]  T. Strom,et al.  Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. , 2011, American journal of human genetics.

[4]  X. Zhu,et al.  Cloning, sequence, and expression of a cDNA encoding hamster UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase. , 1990, The Journal of biological chemistry.

[5]  E. Beitz,et al.  T(E)Xtopo: shaded membrane protein topology plots in LAT(E)X2epsilon. , 2000, Bioinformatics.

[6]  J. Christianson,et al.  Regulation of Nicotinic Acetylcholine Receptor Assembly , 2003, Annals of the New York Academy of Sciences.

[7]  A. Vincent,et al.  End-plate gamma- and epsilon-subunit mRNA levels in AChR deficiency syndrome due to epsilon-subunit null mutations. , 2001, Brain : a journal of neurology.

[8]  H. Freeze,et al.  Deficiency of UDP‐GlcNAc:Dolichol Phosphate N‐Acetylglucosamine‐1 Phosphate Transferase (DPAGT1) Causes a Novel Congenital Disorder of Glycosylation Type Ij , 2003, Human mutation.

[9]  R. Bretthauer.  Structure, expression, and regulation of UDP-GlcNAc: dolichol phosphate GlcNAc-1-phosphate transferase (DPAGT1). , 2009, Current Drug Targets.

[10]  G. Matthijs,et al.  DPAGT1‐CDG: Report of a patient with fetal hypokinesia phenotype , 2012, American journal of medical genetics. Part A.

[11]  J. Huisman.  The Netherlands , 1996, The Lancet.

[12]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[13]  H. Nomoto,et al.  Carbohydrate structures of acetylcholine receptor from Torpedo californica and distribution of oligosaccharides among the subunits. , 1986, European journal of biochemistry.

[14]  H. Freeze,et al.  Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG‐Ib) , 2000, Human mutation.

[15]  K. Fischbeck,et al.  Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. , 1997, Human molecular genetics.

[16]  W. Tanner,et al.  Protein glycosylation, conserved from yeast to man: a model organism helps elucidate congenital human diseases. , 2006, Angewandte Chemie.

[17]  Thierry Hennet,et al.  Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol‐linked oligosaccharides , 2009, Human mutation.

[18]  Barbara Imperiali,et al.  The expanding horizons of asparagine-linked glycosylation. , 2011, Biochemistry.

[19]  Jacqueline Palace,et al.  Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations , 2012, Journal of Neurology.

[20]  S. Schiaffino.  Tubular aggregates in skeletal muscle: Just a special type of protein aggregates? , 2012, Neuromuscular Disorders.

[21]  T. Nishizaki,et al.  N-glycosylation at the conserved sites ensures the expression of properly folded functional ACh receptors. , 1997, Brain research. Molecular brain research.

[22]  I. Zahradník,et al.  Structure and composition of tubular aggregates of skeletal muscle fibres. , 2003, General physiology and biophysics.

[23]  Eric Beitz,et al.  TEXtopo: shaded membrane protein topology plots in LATEX2 , 2000, Bioinform..

[24]  C. Slater,et al.  Reliability of neuromuscular transmission and how it is maintained. , 2008, Handbook of clinical neurology.

[25]  A. Engel.  Current status of the congenital myasthenic syndromes , 2012, Neuromuscular Disorders.

[26]  R. Rossi,et al.  Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG): extending the clinical and molecular spectrum of a rare disease. , 2012, Molecular genetics and metabolism.

[27]  R. Ruff.  Endplate contributions to the safety factor for neuromuscular transmission , 2011, Muscle & nerve.

[28]  A. Vincent,et al.  Utrophin abundance is reduced at neuromuscular junctions of patients with both inherited and acquired acetylcholine receptor deficiencies. , 1997, Brain : a journal of neurology.

[29]  Jacqueline A Palace,et al.  Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. , 2012, American journal of human genetics.

[30]  Paul T. Martin.  Glycobiology of the neuromuscular junction , 2003, Journal of neurocytology.

[31]  J. Marth,et al.  A recessive deletion in the GlcNAc-1-phosphotransferase gene results in peri-implantation embryonic lethality. , 1999, Glycobiology.

[32]  Hanns Lochmüller,et al.  186th ENMC International Workshop: Congenital myasthenic syndromes 24–26 June 2011, Naarden, The Netherlands , 2012, Neuromuscular Disorders.