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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

Departments of Pediatrics (Y.O., C.J.P., T.S., D.B.D.), Clinical Biochemistry (K.S., S.O.), and Medical Genetics (H.F., L.W.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Clinical and Molecular Genetics Unit (L.C.W.), Department of Animal Resource Sciences and Applied Biological Chemistry (T.F., S.-I.T.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, 113-8657 Tokyo, Japan; and Biochemistry, Endocrinology and Metabolism Unit (R.S.), Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, United Kingdom

Address all correspondence and requests for reprints to: David B. Dunger, M.D., University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Hills Road, Cambridge CB2 2QQ, United Kingdom.

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.

Y.O. was supported by a Traveling Fellowship from the Wellcome Trust (London, UK).

Abbreviations: FCS, Fetal calf serum; FISH, fluorescence in situ hybridization; HRP, horseradish peroxidase; IGF1R, type 1 IGF receptor; IR, insulin receptor; IUGR, intrauterine growth retardation; rhIGF-I, recombinant human IGF-I.

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