A naturally occurring E30Q mutation in the Gla domain of protein Z causes its impaired secretion and subsequent deficiency.
Protein Z is a vitamin K-dependent glycoprotein that plays a role in the regulation of coagulation. A nucleotide substitution of G by C in exon II of the protein Z gene, resulting in the replacement of Glu-30 with Gln (E30Q), and a G to A transition at the 79th nucleotide in intron F (IntF79G/A) were heterozygously identified in a patient with a severe thrombotic tendency, whose plasma protein Z level was about 15% of normal. Other vitamin K-dependent coagulation factors were within normal ranges. Glu-30 is one of 13 gamma-carboxylation sites in protein Z and is well conserved among vitamin K-dependent proteins. Expression studies revealed that the E30Q mutant was not released from synthesizing cells, although wild-type protein Z was readily secreted in a vitamin K-dependent fashion. The E30Q mutant was N-glycosylated, gamma-carboxylated, and translocated from the endoplasmic reticulum (ER) to the Golgi in the presence of vitamin K, as was the wild type. Coexpression of E30Q with wild-type protein Z interfered with the secretion of the wild type, while only a minor or no effect was observed on the secretion of factor X and plasminogen. The IntF79A allele has been reported to be also associated with lowered protein Z levels.
Souri
Masayoshi
M
Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585 Japan.
Koseki-Kuno
Shiori
S
Iwata
Hiroki
H
Kemkes-Matthes
Bettina
B
Ichinose
Akitada
A
D019943:Amino Acid Substitution; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D018076:DNA, Complementary; D005260:Female; D006031:Glycosylation; D006801:Humans; D007668:Kidney / Q000166:cytology; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D014162:Transfection; D020246:Venous Thrombosis / Q000235:genetics* / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism
D001798:Blood Proteins; D018076:DNA, Complementary; C026080:plasma protein Z; D014812:Vitamin K