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Protein C deficiency Hong Kong 1 and 2: hereditary protein C deficiency
caused by two mutant alleles, a 5-nucleotide deletion and a missense
mutation
Y Sugahara, O Miura, P Yuen and N Aoki
First Department of Medicine, Tokyo Medical and Dental University, Japan.
We characterized a mutant protein C gene from an individual with no
detectable protein C antigen in blood plasma. Southern blot hybridization
analysis with human protein C cDNA demonstrated neither gross deletion nor
rearrangement of the gene. Sequencing all the exons and exon-intron
boundaries of the gene except the 3' noncoding region showed two mutant
alleles. The one, derived from the mother, represents a deletion of 5
nucleotides (nt) (CCCGC) in the end of exon VI (mutation I), predicted to
result in the generation of a new stop codon due to a reading frameshift
and the premature termination of translation. The other, derived from the
father, represents a point mutation (G to A) in exon IX (mutation II),
resulting in an amino acid substitution, Gly-376(GGC) to Asp(GAC), in the
catalytic domain of the protein. Allele-specific oligonucleotide probe
hybridization confirmed the presence of the two mutations. Mutation I would
result in a truncated polypeptide of 169 amino acid residues that lacks the
heavy chain. Mutation II gives rise to an alteration of a highly conserved
amino acid, Gly-376. These data indicate that this patient is a compound
heterozygote of the two mutant alleles, each one inherited from each
parent. Transient expression assays using COS-7 cells transfected with
mutated protein C expression vectors suggested that each of the two
mutations leads to the protein C deficiency by causing an impairment of
secretion of the respective mutant proteins.
Volume 80,
Issue 1,
pp. 126-133,
07/01/1992
Copyright © 1992 by The American Society of Hematology
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