Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure.

Mutations in the IGF1R gene result in intrauterine growth retardation and postnatal growth failure. The objective of this study was to describe the clinical features of subjects with a mutation in the IGF1R gene and to evaluate the molecular and functional characteristics of a novel IGF1R mutation. Three children with unexplained intrauterine growth retardation (birth weight <-1.5 SD score) and persistent short stature (<-2.0 SD score) were included in the study. Auxological and endocrinological profiles were measured. All coding regions, including the intron-exon boundaries of the IGF1R gene, were amplified via PCR and directly sequenced. To study the functional effect of the IGF1R gene mutation on IGF-I signaling, total IGF1R protein expression, and IGF-I-dependent Akt and ERK phosphorylation were assessed by Western blotting. Two children and their father possessed a novel c.420del (p.A110fsX20) mutation in exon 2 of the IGF1R gene. After recombinant human GH therapy, the growth deficit decreased in these two children. Our data show that IGF-I-induced autophosphorylation of the phosphorylated tyrosine and phosphorylated Akt of IGF1R increased in a dose-dependent manner but did so less efficiently in patients. Array comparative genomic hybridization of chromosome 15 identified a heterozygous deletion of 15q26.2 to 15qter in subject 3. The novel heterozygous mutation described in this study reduced IGF1R expression and represents haploinsufficiency of the IGF1R gene. Our results indicate that this mutation in the IGF1R gene leads to abnormalities in the function of IGF1R and also retards intrauterine and subsequent growth in humans.