This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fang, P. Articles by Rosenfeld, R. G. Search for Related Content PubMed PubMed Citation Articles by Fang, P. Articles by Rosenfeld, R. G. Related Collections Pediatric Endocrinology

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

Department of Pediatrics (P.F., M.A.D., V.H., R.G.R.), Oregon Health and Science University, Portland, Oregon 97239-3098; Division of Pediatric Endocrinology (B.D.J., I.D.S.), University of South Carolina School of Medicine, Columbia, South Carolina 29203; and Oregon National Primate Research Center (C.T.R.), Beaverton, Oregon 97006-3448

Address all correspondence and requests for reprints to: Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: hwav{at}ohsu.edu.

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.