title: A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype.
abstract: Congenital disorders of glycosylation (CDG) are a large group of recessive multisystem disorders caused by impaired protein or lipid glycosylation. The CDG-I subgroup is characterized by protein N-glycosylation defects originating in the endoplasmic reticulum. The genetic defect is known for 17 different CDG-I subtypes. Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies. In this study, we report a non-consanguineous family with two affected adults presenting with a relatively mild phenotype consisting of moderate ID, epilepsy, hypotonia, aggressive behavior and balance problems. Exome sequencing revealed a compound heterozygous missense mutation, c.85A>T (p.I29F) and c.503T>C (p.L168P), in the DPAGT1 gene. The affected amino acids are located in the first and fifth transmembrane domains of the protein. Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect. Our results show that the clinical spectrum of DPAGT1-CDG is much broader than appreciated so far.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.forename: Mohsin
authors.initials: M
authors.lastname: Shahzad
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Monique
authors.initials: M
authors.lastname: van Scherpenzeel
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Attia
authors.initials: A
authors.lastname: Razzaq
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Zahoor
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
mesh_terms: D000328:Adult; D018981:Congenital Disorders of Glycosylation / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome / Q000235:genetics; D005260:Female; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010641:Phenotype; D014168:Transferrin / Q000378:metabolism
chemical_list: D014168:Transferrin; D017351:N-Acetylglucosaminyltransferases; C047835:dolichyl-phosphate alpha-N-acetylglucosaminyltransferase