DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies.
OBJECTIVE
To investigate patients with DPAGT1 (UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase 1)-associated myasthenic syndrome.


METHODS
We performed exome and Sanger sequencing, determined glycoprotein expression in patient muscles, assessed pathogenicity of the mutant proteins by examining their expression and enzymatic activity in transfected cells, evaluated structural changes in muscle and the neuromuscular junction, and examined electrophysiologic aspects of neuromuscular transmission in vitro.


RESULTS
Patients 1 and 2, 16 and 14 years of age, had progressive fatigable weakness since infancy and are intellectually disabled. Patient 3, a less severely affected brother of patient 1, also has autistic features. Each patient harbors 2 novel heteroallelic mutations in DPAGT1, an enzyme subserving protein N-glycosylation. Patients 1 and 3 harbor Met1Leu, which reduces protein expression, and His375Tyr, which decreases enzyme activity. Patient 2 carries Val264Met, which abolishes enzyme activity, and a synonymous Leu120Leu mutation that markedly augments exon skipping, resulting in some skipped and infrequent nonskipped alleles. Therefore, the nonskipped allele rescues the phenotype. Intracellular microelectrode studies indicate combined pre- and postsynaptic defects of neuromuscular transmission with evidence for somatic mosaicism in patient 2. Structural studies reveal hypoplastic endplates, fiber-type disproportion, tubular aggregates, and degeneration of muscle fiber organelles resulting in autophagocytosis.


CONCLUSIONS
DPAGT1 myasthenia affects multiple parameters of neuromuscular transmission, causes fiber-type disproportion and an autophagic myopathy, and can be associated with intellectual disability. We speculate that hypoglycosylation of synapse-specific proteins causes defects in central as well as motor synapses.
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN. selcen.duygu@mayo.edu.
Duygu
D
Selcen
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Xin-Ming
XM
Shen
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Joan
J
Brengman
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Ying
Y
Li
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Anthony A
AA
Stans
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Eric
E
Wieben
From the Departments of Neurology and Neuromuscular Research Laboratory (D.S., X.-M.S., J.B., A.G.E.), Biomedical Informatics and Statistics (Y.L.), Orthopedic Surgery (A.A.S.), and Biochemistry and Molecular Biology (E.W.), Mayo Clinic, Rochester, MN.
Andrew G
AG
Engel
D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D013569:Synapses / Q000235:genetics / Q000378:metabolism
D017351:N-Acetylglucosaminyltransferases; C047835:dolichyl-phosphate alpha-N-acetylglucosaminyltransferase