A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
Lysyl hydroxylase 3 (LH3, encoded by PLOD3) is a multifunctional enzyme capable of catalyzing hydroxylation of lysyl residues and O-glycosylation of hydroxylysyl residues producing either monosaccharide (Gal) or disaccharide (Glc-Gal) derivatives, reactions that form part of the many posttranslational modifications required during collagen biosynthesis. Animal studies have confirmed the importance of LH3, particularly in biosynthesis of the highly glycosylated type IV and VI collagens, but to date, the functional significance in vivo of this enzyme in man is predominantly unknown. We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance. One mutation dramatically reduced the sugar-transfer activity of LH3, whereas another abrogated lysyl hydroxylase activity; these changes were accompanied by reduced LH3 protein levels in cells. The disorder has a unique phenotype causing severe morbidity as a result of features that overlap with a number of known collagen disorders.
Salo
Antti M
AM
Department of Biochemistry, University of Oulu, PO Box 3000, FI-90014 University of Oulu, Finland.
Cox
Helen
H
Farndon
Peter
P
Moss
Celia
C
Grindulis
Helen
H
Risteli
Maija
M
Robins
Simon P
SP
Myllylä
Raili
R
D000293:Adolescent; D001483:Base Sequence; D003094:Collagen / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000235:genetics*; D005192:Family Health; D005260:Female; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics*; D017422:Sequence Analysis, DNA
D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase