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.