Familial Short Stature Caused by Haploinsufficiency of the Insulin-Like Growth Factor I Receptor due to Nonsense-Mediated Messenger Ribonucleic Acid Decay

Background: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R), a widely expressed, cell surface tyrosine kinase receptor. Five cases of heterozygous mutations in the IGF1R gene have been identified in patients with varying degrees of intrauterine and postnatal growth retardation. Objective: The objective of the study was the analysis of the IGF1R gene in a short-statured patient and his affected family members. Patient: The male patient, with a height of -3.1 SD score (SDS; aged 12 yr), had normal circulating levels of GH binding protein, IGF-I, and IGF binding protein-3. His mother (-4.6 SDS), one of his siblings (-1.94 SDS), and several other maternal family members were also short statured. Results: The patient, his mother, and the short-statured sibling carry a novel heterozygous 19-nucleotide duplication within exon 18 of the IGF1R gene, which introduces a premature termination codon at codon 1106 of the IGF1R open reading frame on one allele. Analyses of the primary dermal fibroblasts derived from the patient and family members indicated that the IGF1R mRNA expressed from the mutant allele was degraded through the nonsense-mediated mRNA decay pathway, resulting in reduced amount of wild-type IGF1R protein and, subsequently, diminished activation of the IGF1R pathway. Conclusions: The mutation results in haploinsufficiency of IGF1R protein due to nonsense-mediated mRNA decay and is associated with familial short stature. (J Clin Endocrinol Metab 94: 1740-1747, 2009)