TMEM165 deficiency causes a congenital disorder of glycosylation.
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.
Centre National de la Recherche Scientifique UMR, Structural and Functional Glycobiology Unit, University of Lille, Institut Fédératif de Recherche, Villeneuve D'Ascq, France.
François
F
Foulquier
Mustapha
M
Amyere
Jaak
J
Jaeken
Renate
R
Zeevaert
Els
E
Schollen
Valérie
V
Race
Riet
R
Bammens
Willy
W
Morelle
Claire
C
Rosnoblet
Dominique
D
Legrand
Didier
D
Demaegd
Neil
N
Buist
David
D
Cheillan
Nathalie
N
Guffon
Pierre
P
Morsomme
Willem
W
Annaert
Hudson H
HH
Freeze
Emile
E
Van Schaftingen
Miikka
M
Vikkula
Gert
G
Matthijs
D000293:Adolescent; D017920:Antiporters; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D012867:Skin / Q000166:cytology
D017920:Antiporters; D027682:Cation Transport Proteins; D008565:Membrane Proteins; C575014:TMEM165 protein, human