A MUTATION IN THE B-CHAIN CODING REGION IS ASSOCIATED WITH IMPAIRED PROINSULIN CONVERSION IN A FAMILY WITH HYPERPROINSULINEMIA
A MUTATION IN THE B-CHAIN CODING REGION IS ASSOCIATED WITH IMPAIRED PROINSULIN CONVERSION IN A FAMILY WITH HYPERPROINSULINEMIA
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DOI：
10.1073/pnas.84.8.2194
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发表时间：
1987-04-01
影响因子：
11.1
通讯作者：
STEINER, DF
中科院分区：
文献类型：
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作者：
CHAN, SJ;SEINO, S;STEINER, DF
Gruppuso等人。书名/作者声明：[Gruppuso，P.，Gordon，P.，Kahn，C.R.，Cornblath，M.，Zeller，W.P.和Schwartz，R.(1984)N.Engl.J.Med.311,629-634]最近描述了一个常染色体显性遗传的高胰岛素原血症家系，提示胰岛素原分子的结构异常是这种疾病的基础。然而，与之前两个有类似症状的家族不同，这个家族中的血清胰岛素原物质似乎不是中间转换产物，而是从几个标准来看表现得像正常的人类胰岛素原。为了进一步确定这种疾病的特征，我们分离并测序了先证者的胰岛素基因。将白细胞DNA克隆到λgt-Wes中，通过空斑杂交获得含有两个胰岛素等位基因MD41和MD51的重组体。对λMD51的DNA测序表明，它包含人胰岛素原的正常编码序列。然而，对λMD41的序列分析揭示了胰岛素原10位密码子(CAC.fwdarw.GAC)的单核苷酸替换，该替换预测了胰岛素B链区天冬氨酸与组氨酸的交换。在第二个受影响的家族成员(先证者S的父亲)的胰岛素等位基因中也发现了该突变。这些结果与Elbein等人[Elbein，S.C.，Gruppuso，P.，Schwartz，R.Skolnick，M.和Permut，M.A.(1985)糖尿病34,821-824]的连锁分析强烈表明该突变是该家族中高胰岛素原血症的原因。胰岛素原向胰岛素的转化抑制可能与[Asp10]原的折叠和/或自结合特性改变有关。
Gruppuso et al. [Gruppuso, P. A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. and Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into .lambda.gt-WES and recombinants containing the two insulin alleles, .lambda.MD41 and .lambda.MD51, were isolated by plaque hybridization. DNA sequencing of .lambda.MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of .lambda.MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC.fwdarw.GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus''s father). These results, along with the linkage analysis of Elbein et al. [Elbein, S. C., Gruppuso, P., Schwartz, R. Skolnick, M. and Permutt, M. A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin.