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Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation.

TitleHeterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation.
Publication TypeJournal Article
Year of Publication2010
AuthorsKruis, T., Klammt J., Galli-Tsinopoulou A., Wallborn T., Schlicke M., Müller E., Kratzsch J., Körner A., Odeh R., Kiess W., & Pfäffle R.
JournalJ Clin Endocrinol Metab
Date Published2010 Mar
KeywordsAdiponectin, Blotting, Western, Cells, Cultured, Diabetes Mellitus, Type 2, Enzyme-Linked Immunosorbent Assay, Failure to Thrive, Female, Fetal Growth Retardation, Genetic Association Studies, Heterozygote, Humans, Infant, Newborn, Infant, Small for Gestational Age, Insulin-Like Growth Factor I, Microcephaly, Mutation, Pedigree, Phosphorylation, Receptor, IGF Type 1, Signal Transduction, Transfection

BACKGROUND: IGF-I receptor (IGF1R) plays an essential role in human intrauterine and postnatal development. Few heterozygous mutations in IGF1R leading to IGF-I resistance and intrauterine and postnatal growth retardation have been described to date.OBJECTIVE: The clinical and functional relevance of a novel heterozygous IGF1R mutation identified in a girl with short stature and six relatives was evaluated.PATIENTS: Affected individuals showed birth lengths between -1.40 and -1.82 sd score (SDS) and birth weights between -1.84 and -2.19 SDS. Postnatal growth retardation ranged between -1.51 and -3.93 height SDS. Additional phenotypic findings were variable including microcephaly, clinodactyly, delayed menarche, and diabetes mellitus type 2. Genetic analyses were initiated due to elevated IGF-I levels of the girl.RESULTS: Denaturing HPLC screening and direct DNA sequencing revealed a heterozygous G3464C IGF1R mutation in exon 19 located within a phylogenetically conserved motif of the kinase domain. The resultant mutation of glycine 1125 to alanine (G1125A) did not affect IGF1R protein expression in transiently transfected COS-7 cells and Igf1R deficient mouse fibroblasts but abrogated IGF-I-induced receptor autophosphorylation and phosphorylation of downstream kinases protein kinase B/Akt and MAPK/Erk (mouse proteins are reported). Cotransfection of wild-type and mutant IGF1R resulted in reduced autophosphorylation of 36 +/- 10% of wild-type levels, suggesting a partial dominant-negative effect.CONCLUSION: The identified G1125A mutation results in a kinase-deficient IGF1R, which is likely to cause the phenotype of intrauterine and postnatal growth retardation.

Alternate JournalJ. Clin. Endocrinol. Metab.
PubMed ID20103656


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