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


METHODS
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.
Kawashima
Yuki
Y
Division of Pediatrics and Perinatology, Tottori University, 36-1, Nishi-machi, Yonago 683-8504, Japan.
Kanzaki
Susumu
S
Yang
Fan
F
Kinoshita
Tomoe
T
Hanaki
Keiichi
K
Nagaishi
Jun-Ichi
J
Ohtsuka
Yoshihiko
Y
Hisatome
Ichirou
I
Ninomoya
Haruaki
H
Nanba
Eiji
E
Fukushima
Toshiaki
T
Takahashi
Shin-Ichiro
S
D000293:Adolescent; D000328:Adult; D001827:Body Height / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000096:biosynthesis; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
D007334:Insulin-Like Growth Factor I; D004247:DNA; D017526:Receptor, IGF Type 1