Severe ALG8-CDG (CDG-Ih) associated with homozygosity for two novel missense mutations detected by exome sequencing of candidate genes.
Posttranslationally glycosylated proteins are important in many biological processes in humans and Congenital disorders of glycosylation (CDGs) are associated with a broad range of phenotypes. Type I CDGs are a group of rare autosomal recessive conditions. To date 17 subtypes have been enzymatically and molecularly characterized. Impaired function of the enzyme dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase encoded by the ALG8 gene, causes ALG8-CDG (CDG-Ih, OMIM #608104). This enzyme facilitates the transfer of a second glucose molecule to a growing lipid-linked oligosaccharide chain, a process that transpires in the endoplasmic reticulum (ER). We present a female patient of consanguineous parents, with pre- and postnatal growth retardation, dysmorphic features, significant developmental delay, visual impairment and an electrophoretic serum transferrin pattern indicative of a type I CDG. Type I CDG subgroup was determined by exome sequencing facilitated by homozygosity analysis. The patient was homozygous for two variants, nine nucleotides apart, in exon 8 of ALG8; c.799T > C [p.Ser267Pro] and c.808T > C [p.Phe270Leu]. Both missense mutations are predicted to affect a conserved region of an intraluminal ER loop of dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase. To our knowledge, the current report describes the ninth published case of ALG8-CDG, contributing to the further delineation of this rare and variable disorder.
Department of Medical Genetics, Oslo University Hospital, Nydalen, Oslo, Norway.
Hanne
H
Sorte
Lars
L
Mørkrid
Olaug
O
Rødningen
Mari Ann
MA
Kulseth
Asbjørg
A
Stray-Pedersen
Gert
G
Matthijs
Valerie
V
Race
Gunnar
G
Houge
Torunn
T
Fiskerstrand
Bjørn
B
Bjurulf
Robert
R
Lyle
Trine
T
Prescott
D000595:Amino Acid Sequence; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D059472:Exome / Q000235:genetics; D005260:Female; D005964:Glucosyltransferases / Q000235:genetics*; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
C473777:ALG8 protein, human; D005964:Glucosyltransferases