Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R.
BACKGROUND
Signaling via the IGF-I receptor (IGF-IR) is crucial for normal prenatal and postnatal growth. The heterozygous IGF-IR mutation Arg59Ter resulted in reduced IGF-IR expression and represents haploinsufficiency of the human IGF1R gene.


OBJECTIVE
We studied clinical and in vitro aspects of a human IGF1R gene dosage effect. We provide detailed clinical data on the two half-brothers and their mother with the Arg59Ter mutation. Arg59Ter and control fibroblasts were examined for functionality of IGF-I and insulin-stimulated receptor phosphorylation and signal transduction.


RESULTS
The two brothers presented with primary microcephaly, mild mental retardation, and intrauterine as well as postnatal growth deficits. After GH therapy (30 microg/kg.d) for 24 months, the growth deficit in the propositus decreased by +1.0 sd. There was no clinical evidence for impaired glucose tolerance or hypoglycemia in all Arg59Ter subjects. In vitro, IGF-IR-deficient Arg59Ter cells expressed less IGF-IR and unchanged insulin receptor (IR) protein. Receptor autophosphorylation and phosphorylation of downstream protein kinase B/Akt exhibited resistance to IGF-I but showed an augmented response to insulin in Arg59Ter cells. Decreased IGF-IR content was accompanied by a reduction of IGF-IR/IR receptor hybrids, and therefore, increased levels of IR/IR homodimers probably explain increased insulin-stimulated receptor autophosphorylation and Akt phosphorylation.


CONCLUSIONS
In vivo and in vitro IGF-I resistance in Arg59Ter subjects and fibroblasts indicates a human IGF1R gene dosage effect involving not only the IGF-IR, but also IGF-IR/IR hybrids. The abundance of both the IGF-IR protein and IGF-IR/IR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.
Pediatric Endocrinology and Diabetes, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, D-13353 Berlin, Germany. klemens.raile@charite.de
K
K
Raile
J
J
Klammt
A
A
Schneider
A
A
Keller
S
S
Laue
R
R
Smith
R
R
Pfäffle
J
J
Kratzsch
E
E
Keller
W
W
Kiess
D001835:Body Weight; D005260:Female; D018628:Gene Dosage; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics*
D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose