The severe short stature in two siblings with a heterozygous IGF1 mutation is not caused by a dominant negative effect of the putative truncated protein

H.A. van Duyvenvoorde, J. van Doorn, J. Koenig, L. Gauguin, W. Oostdijk, J.D. Wade, M. Karperien, C.A.L. Ruivenkamp, M. Losekoot, P.A. van Setten, M.J.E. Walenkamp, C. Noordam, P. de Meyts, J.M. Wit

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Objective: While in previous studies heterozygosity for an Insulin-Like Growth Factor 1 (IGF1) defect only
modestly decreased height and head circumference, we recently reported on two siblings with severe short
stature with a maternally transmitted heterozygous duplication of 4 nucleotides, resulting in a frame shift and
a premature termination codon in the IGF1 gene. In this paper we describe the structural and functional
characteristics of the putative truncated IGF-I protein.

Design: Two children, their mother and maternal grandfather carried the mutation. In addition, two family
members who were not affected were included in the study. Mutant (MT) IGF-I was synthesized in oxidized
and reduced form using two methods. Neutral gel filtration studies were carried out with wild-type (WT) and
synthetic MT IGF-I. Binding analysis of synthetic MT IGF-I to the IGF1R and insulin receptors were performed
with EBNA-293 cells, stably transfected with the IGF-I receptor, and IM9 cells. L6 cells were used to examine
the mitogenic potency and the potential antagonizing effect of synthetic MT IGF-I by [3H]-thymidine
incorporation assays.

Results: In the sera of both the carriers and non-carriers the proportion of 125I-IGF-I that was associated with
the 150 kDa complex was somewhat less (varying between ~37 and ~52%) than in normal pooled serum
(~53−~63%) and, instead, slightly increased amounts of radioactivity were eluted in the 40−50 kDa fraction
(consisting of binary IGF–IGFBP complexes) or remained unbound. Synthetic MT IGF-I did not bind to the
IGF-I receptor, nor antagonize the growth-promoting effect of IGF-I. It did bind to IGFBPs, but was barely
incorporated into 150 kDa complexes. Because in all cases WT IGF-I immunoreactivity was recovered in one
peak, corresponding to the MW of WT IGF-I, i.e. ~7.6 kDa, an interaction of circulating truncated mutant
peptide with WT IGF-I is very unlikely.

Conclusions: There is no evidence that the severe short stature associated with heterozygosity for this novel
IGF1 mutation in children born from a mother with the same mutation is caused by a dominant negative effect
of the truncated protein. We speculate that the growth failure is caused by a combination of partial IGF-I
deficiency, placental IGF-I insufficiency, and other genetic factors.
Original languageEnglish
Pages (from-to)44-50
JournalGrowth hormone & IGF research
Issue number1
Publication statusPublished - 2011


  • IR-104490
  • METIS-283817
  • Heterozygote
  • Human growth hormone
  • Humans
  • Insulin-like growth factor I
  • IGF1
  • GH treatment
  • Growth
  • Microcephaly
  • Mutation
  • Pedigree
  • Short stature


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