Cell Proliferation Activities on Skin Fibroblasts from a Short Child with Absence of One Copy of the Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Gene and a Tall Child with Three Copies of the IGF1R Gene

Abstract

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.

Genetic disorders in the GH–IGF-I axis in mouse and man

“…The phenotype variability in IGF-I insensitivity is most probably caused by differences in remaining IGF-I signaling or by a compensatory mechanism that up-regulates the expression of the normal IGF1R allele. In addition, a gene dose effect seems to play a role in postnatal growth as is demonstrated by the severe postnatal growth failure (K3.5 to K6.3 SDS) of patients with IGF1R haploinsufficiency due to a terminal 15q deletion, including the IGF1R gene (23, 25,26,[28][29][30]. The finding that trisomy of terminal 15q resulting in duplication of the IGF1R gene is associated with tall stature supports this hypothesis (58).…”

“…Stimulated GH secretion was normal in all tested patients (24,26,(28)(29)(30). Apparently, IGF1R haploinsufficiency has no major impact on GH and IGF-I secretion.…”

“…The report of a patient with three copies of the IGF1R gene supports the concept that a gene dose effect plays a role in intrauterine growth. This patient is born at 42 weeks gestational age with a birth weight of 5140 g, a birth length of 60 cm, and a head circumference of 38.5 cm (28).…”

Tetrasomy 15q26: a distinct syndrome or Shprintzen-Goldberg syndrome phenocopy?

“…The binding of IGF-I to its receptor induces receptor autophosphorylation in the intracellular kinase domain of the β-subunit and results in activation of the intrinsic tyrosine kinase activity of the IGF1R. Okubo et al 37 demonstrated increased rates of cell proliferation and autophosphorylation of IGF1R in skin fibroblasts from a patient with duplication of IGFR1 arising from a parental pericentric inversion. Gene dosage for IGF1R is increased in our patients and may result in increased binding of IGFs and overgrowth.…”

Mono-allelic expression of the IGF-I receptor does not affect IGF responses in human fibroblasts

“…It has been suggested that hemizygosity for IGF1R causes primary IGF-I resistance despite normal GH and/or IGF-I levels in sera (12 -23). Nonetheless, limited information exists on the biological response to IGF-I in vitro in cultured cells and in vivo in patients with mono-allelic expression of the IGF-I receptor (18,23,24).…”