Noonan 症候群児に認められた異常プロテインC (Ser250→Asn) : Protein C Sakaiminato

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  • A Novel Mutant Protein C (Protein C Sakaiminato) Caused by an Amino Acid Substitution of Ser250 to Asn in a Noonan Syndrome Child

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The proband was a Noonan syndrome child who had a prolonged activated partial thromboplastin time and low level activities in factors V, VII, VIII, IX, XII, high molecular weight kininogen and plasma prekallikrein. The protein C in plasma of the proband and his healthy father was characterized by normal antigen and amidolytic activity levels but low anticoagulant activity. This suggested that they are type II protein C deficient (Protein C Sakaiminato). DNA sequence analyses of all coding regions in the protein C gene derived from them revealed a substitution from G to A at position 10365 in exon IX (Plutzky J, et al. 1986). This mutation abolished a Sfc I restriction site by changing the nucleotide sequence CTACAG to CTACAA. Thus, in heterozygotes of this mutation, the proband and his father, Sfc I cleavage of PCR-amplified DNA fragments including the mutation site yielded both an undigested 620bp fragment from the mutant allele and the digested 437bp and 183bp fragments from normal allele. This mutation was predicted to cause the substitution of Ser250 (AGC) to Asn (AAC). This region was considered as an exosite which is responsible for the binding of activated protein C to macromolecular substrates such as factors Va and VIIIa. Therefore, this mutation would result in the defect of the substrate recognition mechanism of activated protein C. Furthermore, the Ser250 Asn substitution was predicted to cause the loss of one consensus sequence for glycosylation (Asn248-Tyr-Ser). The influence of a sugar chain delation at Asn248 on the maturation process, catalytic properties or stability of protein C should be studied further in detail.

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