An Increased Membrane Glycoprotein PC-1 in a Werner's Syndrome Patient with Rare Compound Heterozygous Mutations
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概要
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ウェルナー症候群(WS)はインスリン抵抗性を高率に合併する早老症である.本症疑診例の遺伝子変異を検索し,さらにインスリン受容体チロシンキナーゼ阻害物質PC-1活性の面からインスリン抵抗性を検討した.症例は29歳男性で,インスリン抵抗性糖尿病(FPG:137mg/dl,IRI:44μU/ml,GIR:1.21mg/kg/min)と特徴的な身体所見からWSが疑われた.末梢血白血球DNAよりWS遺伝子の変異を調べたところ,WS遺伝子のmutation-4,-6の複合変異を同定した.また,患者由来の培養皮膚腺維芽細胞におけるPC-1活性を測定したところ. PC-1活性は99.0nmo1/mg/minと正常人(42.6±13.8)に比し上昇していた.WS遺伝子の稀な変異を有するWSの1例を見出し,PC-1活性の上昇を確認した.膜糖蛋白PC-1がWSにおけるインスリン抵抗性の一因となっている可能性も示唆された.Diabetes mellitus is known to be one of the common metabolic disorders in the Werner's syndrome (WS). It is thought that intracellular defects at the downstream of receptor signaling step cause insulin resistance in WS patients. Recently a membrane glycoprotein referred to as plasma cell differentiation antigen (PC-1) was speculated to play a role in the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) by inhibiting the signaling mediated by the insulin receptor. Because there is no previous report showing increased PC-1 activity in WS patient, this study was undertaken to determine whether the expression of glycoprotein PC-1 is upregulated in the WS patient. The PC-1 activities of the cultured dermal fibroblasts from a 29-years-old Japanese man with WS, who had a compound heterozygous mutation consisting of mutation-4 and -6, and seven healthy controls were determined. The level of PC-1 activity of the dermal fibroblasts from the WS patient was 99.0 nmol/mg/min, and higher than that of non-diabetic healthy controls, 42.6±13.8 nmol/mg/min (mean±SD). This result suggests that glycoprotein PC-1 may play a role at least in part in the pathogenesis of insulin resistance in a patient with WS, accounting perhaps for a high frequency of diabetes mellitus in WS patients.
- 1999-06-25
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