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目的探讨胰岛素受体基因突变在严重胰岛素抵抗综合征中的发病机制。方法采用PCR对一临床拟诊A型胰岛素抵抗综合征患者胰岛素受体的22个外显子进行扩增并直接测序,测得突变所在外显子后,将其一级亲属的相应外显子进行扩增并直接测序。结果先证者及其父亲均为胰岛素受体第20号外显子R1174W杂合错义突变,另发现先证者胰岛素受体3处外显子纯合同义突变及6处内含子变异。胰岛素受体第20号外显子R1174W杂合子突变引起胰岛素受体β亚基酪氨酸激酶活性下降和自身磷酸化缺陷。结论胰岛素受体第20号外显子R1174W杂合子突变是导致该家系先证者及其父亲严重胰岛素抵抗的主要原因,不排除环境因素及其它基因突变的合并存在造成临床表型差异的可能。
Objective To investigate the pathogenesis of insulin receptor gene mutation in severe insulin resistance syndrome. Methods 22 exons of insulin receptor in patients with type A insulin resistance syndrome were amplified by PCR and sequenced directly. After the exons were detected, the exon of their first degree relatives Amplified and sequenced directly. Results Both probands and their fathers were heterozygous heterozygous mutations of R1174W at exon 20 of insulin receptor. Synonymous mutations in exon 3 of insulin receptor and mutation in 6 introns were also found in probands. R1174W heterozygous mutation at exon 20 of insulin receptor causes a decrease in insulin receptor beta subunit tyrosine kinase activity and defects in autophosphorylation. Conclusion The heterozygous mutation R1174W of exon 20 of insulin receptor is the main reason leading to severe insulin resistance in this family proband and his father. It is not possible to rule out the possibility of clinical phenotypic differences due to the combination of environmental factors and other genetic mutations.