RFT1 deficiency in three novel CDG patients.
The medical significance of N-glycosylation is underlined by a group of inherited human disorders called Congenital Disorders of Glycosylation (CDG). One key step in the biosynthesis of the Glc(3)Man(9)GlcNAc(2)-PP-dolichol precursor, essential for N-glycosylation, is the translocation of Man(5)GlcNAc(2)-PP-dolichol across the endoplasmic reticulum membrane. This step is facilitated by the RFT1 protein. Recently, the first RFT1-deficient CDG (RFT1-CDG) patient was identified and presented a severe N-glycosylation disorder. In the present study, we describe three novel CDG patients with an RFT1 deficiency. The first patient was homozygous for the earlier reported RFT1 missense mutation (c.199C>T; p.R67C), whereas the two other patients were homozygous for the missense mutation c.454A>G (p.K152E) and c.892G>A (p.E298 K), respectively. The pathogenic character of the novel mutations was illustrated by the accumulation of Man(5)GlcNAc(2)-PP-dolichol and by reduced recombinant DNase 1 secretion. Both the glycosylation pattern and recombinant DNase 1 secretion could be normalized by expression of normal RFT1 cDNA in the patients' fibroblasts. The clinical phenotype of these patients comprised typical CDG symptoms in addition to sensorineural deafness, rarely reported in CDG patients. The identification of additional RFT1-deficient patients allowed to delineate the main clinical picture of RFT1-CDG and confirmed the crucial role of RFT1 in Man(5)GlcNAc(2)-PP-dolichol translocation.
Vleugels
Wendy
W
Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, Leuven, Belgium.
Haeuptle
Micha A
MA
Ng
Bobby G
BG
Michalski
Jean-Claude
JC
Battini
Roberta
R
Dionisi-Vici
Carlo
C
Ludman
Mark D
MD
Jaeken
Jaak
J
Foulquier
François
F
Freeze
Hudson H
HH
Matthijs
Gert
G
Hennet
Thierry
T
D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D010641:Phenotype
D008562:Membrane Glycoproteins; C486729:RFT1 protein, human
Biochim Biophys Acta. 1999 Jan 6;1426(2):239-57
9878760
J Inherit Metab Dis. 2008 Dec;31(6):669-72
18949576
Biochem J. 2001 Apr 1;355(Pt 1):245-8
11256970
Curr Mol Med. 2007 Jun;7(4):389-96
17584079
Pediatr Res. 2006 Dec;60(6):643-56
17065563
Biochemistry. 2008 Jul 29;47(30):7937-46
18597486
NeuroRx. 2006 Apr;3(2):254-63
16554263
FEBS J. 2008 Feb;275(4):788-98
18215164
Nature. 2008 Jul 31;454(7204):E3-4; discussion E4-5
18668045
Biochem J. 2002 Mar 1;362(Pt 2):491-8
11853559
Glycobiology. 1993 Apr;3(2):97-130
8490246
J Biol Chem. 1997 Aug 1;272(31):19408-12
9235940
J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S137-9
19267216
Am J Med Genet A. 2007 Jun 15;143A(12):1371-8
17506107
Glycobiology. 2005 Nov;15(11):1084-93
16079417
Arch Dis Child. 1995 May;72(5):445-6
7618917
Annu Rev Genomics Hum Genet. 2007;8:261-78
17506657
Am J Hum Genet. 2008 Mar;82(3):600-6
18313027
EMBO J. 1995 Oct 16;14(20):4949-60
7588624
J Mol Biol. 2001 Jan 19;305(3):567-80
11152613
Nature. 2002 Jan 24;415(6870):447-50
11807558
Glycobiology. 2006 Jun;16(6):91R-101R
16510493
J Inherit Metab Dis. 2000 Mar;23(2):162-74
10801058