Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation

摘要

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.