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


METHODS
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.


CONCLUSIONS
The identified G1125A mutation results in a kinase-deficient IGF1R, which is likely to cause the phenotype of intrauterine and postnatal growth retardation.
Kruis
Tassilo
T
University Hospital for Children and Adolescents, Liebigstrasse 20a, D-04103 Leipzig, Germany.
Klammt
Jürgen
J
Galli-Tsinopoulou
Assimina
A
Wallborn
Tillmann
T
Schlicke
Marina
M
Müller
Eva
E
Kratzsch
Jürgen
J
Körner
Antje
A
Odeh
Rasha
R
Kiess
Wieland
W
Pfäffle
Roland
R
D052242:Adiponectin / Q000097:blood; D015153:Blotting, Western; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005183:Failure to Thrive / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008831:Microcephaly / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
D052242:Adiponectin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1