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- Title
Novel missense mutation in the IGF- I receptor L2 domain results in intrauterine and postnatal growth retardation.
- Authors
Kawashima, Yuki; Higaki, Katsumi; Fukushima, Toshiaki; Hakuno, Fumihiko; Nagaishi, Jun-ichi; Hanaki, Keiichi; Nanba, Eiji; Takahashi, Shin-Ichiro; Kanzaki, Susumu
- Abstract
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 ( R431 L). Method 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 R431 L 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 ( R431 L) 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 R431 L 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. Conclusion A missense mutation ( R431 L) 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.
- Subjects
MISSENSE mutation; INSULIN-like growth factor-binding proteins; FETAL growth retardation; NUCLEOTIDE sequence; TYROSINE; CONFOCAL microscopy
- Publication
Clinical Endocrinology, 2012, Vol 77, Issue 2, p246
- ISSN
0300-0664
- Publication type
Article
- DOI
10.1111/j.1365-2265.2012.04357.x