This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murphy, R. Articles by Hattersley, A. T. Search for Related Content PubMed PubMed Citation Articles by Murphy, R. Articles by Hattersley, A. T. Related Collections Pediatric Endocrinology Diabetes and Insulin Metabolism

Severe Intrauterine Growth Retardation and Atypical Diabetes Associated with a Translocation Breakpoint Disrupting Regulation of the Insulin-Like Growth Factor 2 Gene

Institute of Clinical and Biomedical Sciences (R.M., S.E., L.W.H., A.T.H.), Peninsula Medical School, Exeter EX2 5DW, United Kingdom; Faculty of Medical and Health Sciences (R.M., T.C.), University of Auckland, 1142 Auckland, New Zealand; Wessex Regional Genetics Laboratory (J.B., J.C.) and National Genetics Reference Laboratory (Wessex) (J.C.), Salisbury District Hospital, SalisburySP2 8BJ, United Kingdom; Division of Human Genetics (J.B.), School of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom; IGF and Metabolic Endocrinology Group (J.H.), University of Bristol, Bristol BS13NY United Kingdom; and Wolfson Centre for Translational Research (A.M.U.), Department of Diabetes and Endocrinology, Postgraduate Medical School, University of Surrey, GU2 7XH Surrey United Kingdom

Address all correspondence and requests for reprints to: Andrew T. Hattersley, Professor of Molecular Medicine, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom. E-mail: andrew.hattersley{at}pms.ac.uk.

Context: IGF-II is an imprinted gene (predominantly transcribed from the paternally inherited allele), which has an important role in fetal growth in mice. IGF2 gene expression is regulated by a complex system of enhancers and promoters that determine tissue-specific and development-specific transcription. In mice, enhancers of the IGF2 gene are located up to 260 kb telomeric to the gene. The role of IGF-II in humans is unclear.

Objective: A woman of short adult stature (1.46 m, –3 SD score) born with severe intrauterine growth retardation (1.25 kg at term, –5.4 SD score) and atypical diabetes diagnosed at the age of 23 yr had a balanced chromosomal translocation t(1;11) (p36.22; p15.5). We hypothesized that her phenotype resulted from disruption of her paternally derived IGF2 gene because her daughter who inherited the identical translocation had normal birth weight.

Design: Both chromosomal break points were identified using fluorescent in situ hybridization. Sequence, methylation, and expression of the IGF2 gene was examined. Hyperinsulinemic, euglycemic clamp with glucose tracers and magnetic resonance imaging of the thorax, abdomen, and pelvis were performed.

Results: The 11p15.5 break point mapped 184 kb telomeric of the IGF2 gene. Microsatellite markers confirmed paternal origin of this chromosome. IGF2 gene sequence and methylation was normal. IGF2 gene expression was reduced in lymphoblasts. Clamp studies showed marked hepatic and total insulin resistance. Massive excess sc fat was seen on magnetic resonance imaging despite slim body mass index (21.1 kg/m²).

Conclusions: A break point 184 kb upstream of the paternally derived IGF2 gene, separating it from some telomeric enhancers, resulted in reduced expression in some mesoderm-derived adult tissues causing intrauterine growth retardation, short stature, lactation failure, and insulin resistance with altered fat distribution.

This article has been cited by other articles:

				Y. A. R. White, J. T. Kyle, and A. W. Wood Targeted Gene Knockdown in Zebrafish Reveals Distinct Intraembryonic Functions for Insulin-Like Growth Factor II Signaling Endocrinology, September 1, 2009; 150(9): 4366 - 4375. [Abstract] [Full Text] [PDF]