TMEM165 Deficiency Causes a Congenital Disorder of Glycosylation
Foulquier, François Amyere, Mustapha Jaeken, Jaak Zeevaert, Renate Schollen, Els Race, Valérie Bammens, Riet Morelle, Willy Rosnoblet, Claire Legrand, Dominique Demaegd, Didier Buist, Neil Cheillan, David Guffon, Nathalie Morsomme, Pierre Annaert, Wim Freeze, Hudson H Van Schaftingen, Emile Vikkula, Miikka Matthijs, Gert # ×
American Society of Human Genetics
American Journal of Human Genetics vol:91 issue:1 pages:15-26
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.