Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation
Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation
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DOI：
10.1210/jc.2009-1433
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发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Pfaeffle, Roland
中科院分区：
文献类型：
--
作者：
Kruis, Tassilo;Klammt, Juergen;Pfaeffle, Roland
背景：IGF-I受体（IGF 1 R）在人的宫内和出生后发育中起重要作用。IGF 1 R的杂合突变导致IGF-I抵抗和宫内及出生后生长迟缓的报道很少。目的：对一个身材矮小的女孩和6个亲属中发现的一种新的IGF 1 R杂合突变的临床和功能相关性进行评价。患者：受影响的个体显示出生身长在-1.40和-1.82 SD评分（SDS）之间，出生体重在-1.84和-2.19 SDS之间。出生后生长迟缓的身高SDS范围为-1.51至-3.93。其他的表型结果是可变的，包括小头畸形、指（趾）倾、月经初潮延迟和2型糖尿病。结果：变性HPLC筛选和直接DNA测序显示，位于激酶结构域的一个遗传保守基序内的第19外显子的IGF 1 R杂合G3464 C突变。甘氨酸1125突变为丙氨酸（G1125 A）不影响瞬时转染COS-7细胞和Igf 1 R缺陷小鼠成纤维细胞中的IGF 1 R蛋白表达，但消除了IGF-I诱导的受体自磷酸化和下游激酶蛋白激酶B/Akt和MAPK/Erk（报告了小鼠蛋白）的磷酸化。共转染野生型和突变型IGF 1 R导致减少36 +/- 10%的野生型levels.Conclusion：G1125 A突变的结果在激酶缺陷型IGF 1 R，这是可能导致宫内和出生后生长迟缓的表型的自磷酸化。（临床内分泌代谢杂志95：1137-1142，2010）
Background: IGF-I receptor (IGF1R) plays an essential role in human intrauterine and postnatal development. Few heterozygous mutations in IGF1R leading to IGF-I resistance and intrauterine and postnatal growth retardation have been described to date.Objective: The clinical and functional relevance of a novel heterozygous IGF1R mutation identified in a girl with short stature and six relatives was evaluated.Patients: Affected individuals showed birth lengths between -1.40 and -1.82 SD score (SDS) and birth weights between -1.84 and -2.19 SDS. Postnatal growth retardation ranged between -1.51 and -3.93 height SDS. Additional phenotypic findings were variable including microcephaly, clinodactyly, delayed menarche, and diabetes mellitus type 2. Genetic analyses were initiated due to elevated IGF-I levels of the girl.Results: Denaturing HPLC screening and direct DNA sequencing revealed a heterozygous G3464C IGF1R mutation in exon 19 located within a phylogenetically conserved motif of the kinase domain. The resultant mutation of glycine 1125 to alanine (G1125A) did not affect IGF1R protein expression in transiently transfected COS-7 cells and Igf1R deficient mouse fibroblasts but abrogated IGF-I-induced receptor autophosphorylation and phosphorylation of downstream kinases protein kinase B/Akt and MAPK/Erk(mouse proteins are reported). Cotransfection of wild-type and mutant IGF1R resulted in reduced autophosphorylation of 36 +/- 10% of wild-type levels, suggesting a partial dominant-negative effect.Conclusion: The identified G1125A mutation results in a kinase-deficient IGF1R, which is likely to cause the phenotype of intrauterine and postnatal growth retardation. (J Clin Endocrinol Metab 95: 1137-1142, 2010)