A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

Eur J Hum Genet. 2013 Aug;21(8):844-9. doi: 10.1038/ejhg.2012.257. Epub 2012 Dec 19.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Congenital Disorders of Glycosylation / enzymology
  • Congenital Disorders of Glycosylation / genetics*
  • Congenital Disorders of Glycosylation / pathology
  • DNA Mutational Analysis / methods
  • Exome / genetics
  • Female
  • Glycosylation
  • Heterozygote*
  • Humans
  • Male
  • Mutation, Missense*
  • N-Acetylglucosaminyltransferases / genetics*
  • Phenotype
  • Transferrin / metabolism

Substances

  • Transferrin
  • N-Acetylglucosaminyltransferases
  • dolichyl-phosphate alpha-N-acetylglucosaminyltransferase