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
Autor: | Monique Losekoot, Claudia A. L. Ruivenkamp, Lisbeth Gauguin, P.A. van Setten, M.J.E. Walenkamp, P. De Meyts, J. van Doorn, Cees Noordam, Marcel Karperien, Jan M. Wit, H.A. van Duyvenvoorde, J. Koenig, Wilma Oostdijk, John D. Wade |
---|---|
Přispěvatelé: | Faculty of Science and Technology, Pediatric surgery, Other Research |
Jazyk: | angličtina |
Rok vydání: | 2011 |
Předmět: |
Male
medicine.medical_specialty Heterozygote Endocrinology Diabetes and Metabolism Mutant Molecular Sequence Data Mutation Missense Dwarfism Growth medicine.disease_cause Short stature Frameshift mutation Loss of heterozygosity Endocrinology GH treatment Internal medicine medicine Protein Isoforms Humans Amino Acid Sequence METIS-283817 IR-104490 Receptor Child Insulin-like growth factor 1 receptor Genes Dominant Mutation biology Base Sequence Human growth hormone Siblings IGF1 Insulin-like growth factor I Body Height Pedigree Insulin receptor Mitochondrial medicine [IGMD 8] biology.protein Microcephaly Female medicine.symptom |
Zdroj: | None Growth Hormone & Igf Research, 21, 1, pp. 44-50 Growth Hormone & Igf Research, 21, 44-50 Growth hormone & IGF research, 21(1), 44-50. Churchill Livingstone Growth Hormone and IGF Research, 21(1), 44-50. Churchill Livingstone van Duyvenvoorde, H A, van Doorn, J, Koenig, J, Gauguin, L, Oostdijk, W, Wade, J D, Karperien, M, Ruivenkamp, C A L, Losekoot, M, van Setten, P A, Walenkamp, M J E, Noordam, C, De Meyts, P & Wit, J M 2011, ' 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 ', Growth Hormone and IGF Research, vol. 21, no. 1, pp. 44-50 . https://doi.org/10.1016/j.ghir.2010.12.004 |
ISSN: | 1096-6374 |
DOI: | 10.1016/j.ghir.2010.12.004 |
Popis: | Item does not contain fulltext 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 [(3)H]-thymidine incorporation assays. RESULTS: In the sera of both the carriers and non-carriers the proportion of (125)I-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. |
Databáze: | OpenAIRE |
Externí odkaz: |