TMEM165 deficiency causes a congenital disorder of glycosylation

Am J Hum Genet. 2012 Jul 13;91(1):15-26. doi: 10.1016/j.ajhg.2012.05.002. Epub 2012 Jun 7.

Abstract

Protein glycosylation is a complex process that depends not only on the activities of several enzymes and transporters but also on a subtle balance between vesicular Golgi trafficking, compartmental pH, and ion homeostasis. Through a combination of autozygosity mapping and expression analysis in two siblings with an abnormal serum-transferrin isoelectric focusing test (type 2) and a peculiar skeletal phenotype with epiphyseal, metaphyseal, and diaphyseal dysplasia, we identified TMEM165 (also named TPARL) as a gene involved in congenital disorders of glycosylation (CDG). The affected individuals are homozygous for a deep intronic splice mutation in TMEM165. In our cohort of unsolved CDG-II cases, we found another individual with the same mutation and two unrelated individuals with missense mutations in TMEM165. TMEM165 encodes a putative transmembrane 324 amino acid protein whose cellular functions are unknown. Using a siRNA strategy, we showed that TMEM165 deficiency causes Golgi glycosylation defects in HEK cells.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antiporters
  • Cation Transport Proteins
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Congenital Disorders of Glycosylation / genetics*
  • Dwarfism / genetics
  • Female
  • Fibroblasts
  • Golgi Apparatus / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Proteins / genetics*
  • Mutation*
  • Pedigree
  • Skin / cytology

Substances

  • Antiporters
  • Cation Transport Proteins
  • Membrane Proteins
  • TMEM165 protein, human