A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene
A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene
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DOI：
10.2337/diabetes.53.6.1592
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发表时间：
2004-06-01
期刊：
影响因子：
7.7
通讯作者：
Beck-Nielsen, H
中科院分区：
文献类型：
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作者：
Hojlund, K;Hansen, T;Beck-Nielsen, H
最近，常染色体显性遗传的家族性高胰岛素血症的各种亚型的病因学特征。在目前的研究中，我们描述了一种新型低血糖的遗传学和代谢表型，在一个明显常染色体显性遗传的大家系中。在对先证者、她的母亲和一个妹妹进行初步调查后，这项研究扩展到了三代人中的19名家庭成员。通过5小时口服葡萄糖耐量试验(OGTT)和正常血糖-高胰岛素钳夹试验评估6名受试者和6名对照受试者的糖耐量。对所有家系成员的基因组DNA进行连锁分析和突变分析，以确定低血糖的遗传原因。所有受影响的家庭成员均表现为餐后低血糖、空腹高胰岛素血症和血清胰岛素与C肽比值升高。5小时的OGTT显示高胰岛素血症低血糖，钳位研究显示与对照受试者相比，受影响的家族成员的胰岛素敏感性和血清胰岛素清除量降低。连锁分析和随后的突变筛查显示，胰岛素受体基因酪氨酸激酶区域的错义突变(Arg1174Gln)与疾病表型(优势对数[LOD]得分3.21)共分离。综上所述，我们报告了一种新的常染色体显性遗传的高胰岛素血症综合征。这些发现表明严重的餐后低血糖、胰岛素抵抗和胰岛素清除障碍并存，并建议低血糖应被认为是与胰岛素受体基因杂合子突变有关的表型。
Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinelnic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.