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Mutant IGF-1R as Cause for Familial Growth Failure« Back to Volume 23, Issue 2, June 2007 - Table of Contents Inagaki et al identified a family in which 2 members had severe growth failure and a mutant type 1 insulin-like growth factor receptor (IGF-1R). A 13.6-year-old girl presented with growth failure (height z-score –5 SD, sitting height z-score –5.2 SD, and weight z-score –2.5 SD), Tanner stage 2 pubertal development, and delayed bone age (9.7 years). She had experienced prenatal growth failure (birth length –4.9 SD, birth weight –3.1 SD), triangular facies, and acromicria. The father's height was –2.2 SD, the mother's height was –5.7 SD, and they were nonconsanguineous. A maternal aunt's height was –5.7 SD and she seemed otherwise healthy. The patient's 2.5-year-old brother had a height of –1.2 SD. The patient had an elevated basal IGF-I level (404 ng/mL), normal growth hormone (GH) response to clonidine stimulation, and no increase in either her IGF-I level after 4 days of GH treatment or her height z-score after 6 of months GH treatment (0.07 mg/kg/day). Inagaki et al then performed in vitro studies to ascertain the molecular mechanism of this family's growth failure. Sequencing revealed substitution of the phylogenetically highly conserved arginine at position 481 to glutamate (R481Q) in the IGF-1R of both the patient and the maternal aunt. This arginine is in the N-terminal fibronectin type III domain, and situated near the first disulfide bond (Cys 514) between the 2 α-subunits. Either wild-type or R481Q IGF-1R was over-expressed in NIH-3T3 fibroblasts to conduct functional assays. R481Q IGF-1R altered neither surface expression nor ligand binding capacity. However, as demonstrated by Western blotting under reducing and non-reducing conditions, the mutant receptor had incomplete dimerization likely related to impairment of that first disulfide bond; the mutant, but not wild-type, IGF-1R showed monomeric forms of the β-subunit under non-reducing conditions. Further, compared to wild-type, R481Q IGF-1R had blunted IGF-I induction of IGF-1R autophosphorylation, p42/44MAPK phosphorylation, Akt phosphorylation, and cellular proliferation. Thus, the authors concluded that R481Q disturbs the first disulfide bond of IGF-1R, thereby impairing its dimerization and ligand-stimulated conformational change that is required for signal transduction. This translated clinically into IGF-I resistance and growth failure. Editor’s CommentThe authors astutely recognized the severe pre- and post-natal growth failure of their patient as indicative of reduced IGF-I activity; measurement of basal IGF-I concentration quickly ruled out IGF-I deficiency in favor of IGF-I resistance. The authors are to be commended on their detective work, which led to the discovery of a novel mechanism of IGF-I resistance that joins the short list of previously reported IGF-1R mutations. This illustrative case also highlights the importance of obtaining a good family history in the evaluation of a poorly growing child. Most often, we ascribe similar multigenerational height z-scores to familial short stature, which is considered a normal variant. However, when the growth failure is severe and affects a subset of relatives, as exemplified by this patient's family, an inherited growth defect should be considered. Another example would be autosomal dominant (type 2) isolated GH deficiency.1,2 Although the child may be short “like the parent,” it is possible that they are sharing an underlying pathologic process. Adda Grimberg, MD References - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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