Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation.
BACKGROUND
IGFs play key roles in intrauterine and postnatal growth through the IGF-I receptor (IGF-IR). We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF-IR (R431L).


METHODS
We analysed the nucleotide sequences of the IGF1R gene of the family. We prepared R(-)  cells (fibroblasts with targeted disruption of the IGF-IR gene) expressing wild-type or R431L IGF-IR and performed functional analyses by evaluating IGF-I binding, IGF-I-stimulated DNA synthesis, tyrosine phosphorylation of IGF-IR and its substrates, and internalization by measuring [(125) I]IGF-I internalization. We also performed confocal microscopy analysis.


RESULTS
We identified a family bearing a new heterozygous missense mutation at the L2 domain of IGF-IR (R431L) through an 8-year-old girl and her mother, both born with intrauterine growth retardation. In experiments conducted using cells homozygously transfected with the IGF-IR R431L mutation; (i) IGF-I binding was not affected; (ii) DNA synthesis induced by IGF-I was decreased; (iii) IGF-IR internalization stimulated by IGF-I was decreased and (iv) IGF-I-stimulated tyrosine phosphorylation was reduced IGF-IR by low concentrations of IGF-I and on insulin receptor substrate (IRS)-1 and IRS-2.


CONCLUSIONS
A missense mutation (R431L) leads to the inhibition of cell proliferation, attenuation of IGF signalling and decrease in internalization of IGF-IR. The results of this study suggest a novel link between a mutation at the IGF-IR L2 domain and intrauterine and postnatal growth retardation.
Division of Pediatrics & Perinatology, Research Center for Bioscience and Technology, Tottori University Faculty of Medicine, Yonago, Japan. yuki.kawashima@med.tottori-u.ac.jp
Yuki
Y
Kawashima
Katsumi
K
Higaki
Toshiaki
T
Fukushima
Fumihiko
F
Hakuno
Jun-ichi
J
Nagaishi
Keiichi
K
Hanaki
Eiji
E
Nanba
Shin-Ichiro
S
Takahashi
Susumu
S
Kanzaki
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D020125:Mutation, Missense; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1