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Mutation at Cleavage Site of Insulin-Like Growth Factor Receptor in a Short-Stature Child Born with Intrauterine Growth Retardation

Divisions of Pediatrics and Perinatology (Y.K., S.K., T.K., K.H., J.N.) and Molecular Medicine and Therapeutics (I.H.) and Department of Neurobiology (H.N.), Faculty of Medicine and Gene Research Center (E.N.), Tottori University, Yonago 683-8504, Japan; Mitsubishi Kagaku BCL, Inc. (Y.O.), Tokyo 174-8555, Japan; Department of Animal Sciences and Applied Biological Chemistry (T.F., S.-I. T.), The University of Tokyo, Tokyo 113-8657, Japan; and Department of Pediatrics (F.Y.), West China Second University Hospital, Sichuan University, Chengdu 610041, China

Address all correspondence and requests for reprints to: Susumu Kanzaki, M.D., Ph.D., Division of Pediatrics and Perinatology, Tottori University, 36-1, Nishi-machi, Yonago 683-8504, Japan. E-mail: smkanzak{at}grape.med.tottori-u.ac.jp.

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 ß-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 ß-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 10⁶ vs. 1.14 ± 0.12 x 10⁶ sites per cell; P < 0.05); and 4) both IGF-I-stimulated [³H]thymidine incorporation and IGF-IR ß-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.

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