Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation

J Clin Endocrinol Metab. 2005 Aug;90(8):4679-87. doi: 10.1210/jc.2004-1947. Epub 2005 May 31.

Abstract

Context: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth.

Objective: We hypothesized that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR).

Patients: Twenty-four children with unexplained IUGR (birth weight < -1.5 SD) and short stature (<-2.0 SD) were screened for abnormalities of the IGF-IR gene.

Methods: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and beta-subunit autophosphorylation.

Results: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 +/- 26% of normal) and less mature beta-subunit protein (63 +/- 12%); 3) [125I]IGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 +/- 0.16 x 10(6) vs. 1.14 +/- 0.12 x 10(6) sites per cell; P < 0.05); and 4) both IGF-I-stimulated [3H]thymidine incorporation and IGF-IR beta-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05).

Conclusions: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Body Height / genetics*
  • Child
  • Child, Preschool
  • DNA / biosynthesis
  • Female
  • Fetal Growth Retardation / genetics*
  • Fibroblasts / metabolism
  • Heterozygote
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mutation, Missense*
  • Pedigree
  • Phosphorylation
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism

Substances

  • Insulin-Like Growth Factor I
  • DNA
  • Receptor, IGF Type 1