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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0819
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 11 4373-4380
Copyright © 2008 by The Endocrine Society

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

R. Murphy, J. Baptista, J. Holly, A. M. Umpleby, S. Ellard, L. W. Harries, J. Crolla, T. Cundy and A. T. Hattersley

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.


   Abstract
Top
 Abstract
Introduction
 Case report
 Patients and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Case report
 Patients and Methods
 Results
 Discussion
 References
 
IGF-II has been shown to have an important role in regulating intrauterine growth in animal studies (1, 2). IGF2 gene expression is regulated by a complex system of enhancers and promoters that determine tissue-specific and development-specific transcription (3, 4). The gene is also subject to a complex methylation process that silences (or imprints) the maternal allele, so in utero and in most tissues postnatally only the paternal allele is expressed (5, 6, 7). Maternal demethylation of the IGF2 gene region is the predominant cause of Beckwith-Wiedemann syndrome (BWS), which is characterized by somatic overgrowth, congenital malformations, and tumor predisposition (8). Paternal demethylation of the IGF2 gene regulatory region has been described in some children with Silver-Russell syndrome (SRS), who have intrauterine growth retardation, short stature, skeletal asymmetry, and clinodactyly (9) (see Table 1Go). In this report we describe the distinctive phenotype of a woman with a balanced chromosomal translocation of paternal origin, disrupting the regulatory region of the IGF2 gene at 11p15.5.


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  		TABLE 1. GH axis genes associated with growth retardation in humans

 

   Case report
Top
 Abstract
 Introduction
 Case report
Patients and Methods
 Results
 Discussion
 References
 
The patient was born at 40 wk gestation after an uneventful pregnancy to a healthy, nonsmoking mother. At birth she had severe symmetric growth retardation with a birth weight (1.25 kg) that was 5.4 SD below the mean in normal subjects. Despite her extremely small size she had no neonatal morbidity and no features of SRS (Fig. 1AGo). Her early postnatal growth (Fig. 1BGo) and intellectual development were normal. Thelarche and pubarche began at 8 yr and menarche at 10 yr. Her adult height was 1.455 m, 3 SD below the normal mean [sex adjusted midparental height –0.09 SD score (SDS)], with proportionate reduction of both upper and lower body segments.


Figure 1
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  		FIG. 1. Paternal chromosome of origin in proband using microsatellite markers. Haplotype mapping using microsatellite markers close to the break point at 11p15.5. The microsatellites D11S922, D11S4046, and D11S4088 were amplified using FAM-labeled primers and analyzed on an ABI 3100 capillary electrophoresis instrument (Applied Biosystems). Haplotypes were constructed using peak size data to reflect number of microsatellite repeats at each locus, coded as A, B, C, etc. Because the daughter (III-4) of the proband (II-1) was known to have inherited the balanced translocation from her mother, her haplotype B, F, K marked the derivative chromosome 11 (harboring the translocation). Because this haplotype was not inherited from the proband’s mother (I-1), this implied that the balanced translocation in the proband was paternal (I-2) in origin.

 
Diabetes was diagnosed at the age of 23 when she had a body mass index of 21.1 kg/m2, and waist to hip ratio of 0.81. There was no acanthosis nigricans. Her blood pressure (110/80 mm Hg) and fasting lipid profile (total cholesterol 4.6 mmol/liter, high-density lipoprotein 1.2 mmol/liter, high-density lipoprotein 2.6 mmol/liter, triglycerides 1.8 mmol/liter) were normal. She was managed initially with diet and oral hypoglycemic agents (sulfonylureas for 5 yr, then additional metformin for 1 yr). Nocturnal insulin was added after 6 yr for mildly elevated fasting blood glucose (8–9 mmol/liter) when her glycosylated hemoglobin was 6.8%. At the age of 31 yr, she desired pregnancy and hence changed to a basal-bolus insulin regimen. After three first-trimester pregnancy losses, karyotyping in the patient revealed a balanced chromosomal translocation: t(1;11)(p36.22;p15.5). To avoid further spontaneous miscarriages resulting from a fetus carrying an unbalanced translocation, she underwent in vitro fertilization with preimplantation genetic diagnosis and implantation of a blastocyst not carrying an unbalanced translocation. Throughout pregnancy her glycemic control was excellent (glycosylated hemoglobin <6.5%). Serial ultrasound scans demonstrated normal fetal growth (~50th centile). She went into labor at 29 wk gestation and delivered a baby girl (III-4), weighing 1.24 kg (0.01 SDS).

Postpartum the patient was unable to express breast milk despite a normally elevated serum prolactin (3744 ng/ml), additional domperidone therapy, and nipple stimulation with an electric breast pump. Cytogenetic studies of the patient’s daughter (III-4) showed she had inherited the identical balanced chromosomal translocation from her mother and had normal postnatal growth (Fig. 1BGo). After a subsequent pregnancy, the patient again had complete lactational failure. This second baby (III-5) had normal intrauterine growth and was delivered at 34 wk weighing 1.96 kg (–0.6 SDS) with normal female karyotype (Fig. 2Go).


Figure 2
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  		FIG. 2. Genetic studies composite. A, Dual FISH image of the proband’s metaphases. The chromosome 11 centromeric probe (in green) hybridizes to both the normal and the derivative chromosomes der (11 ). The BAC clone RP11–534I22 (in red) is split by the break point, showing a signal on the normal 11 and on both der (11 ) and der (1 ). B, Scale diagram of break point region relative to IGF2 gene and its enhancers (adapted from Ensembl web site http://www.ensembl.org). BAC and fosmid clone positions obtained from the University of California Santa Cruz Genome Browser (http://genome.ucsc.edu) and Ensembl as specified in online supplemental Table 2 (National Center for Biotechnology Information build 36.1). IGF2 enhancer positions obtained from Gabory et al. (16 ). SYT8, Synaptotagmin 8; TNNT3, troponin T3, skeletal, fast; MRPL23, mitochondrial ribosomal protein L23; TNNI2, troponin I2, skeletal, fast; LSP1, lymphocyte specific protein 1; INS, insulin; IGF2, IGF-II; IGF2AS, IGF-II antisense. C, The graph illustrates the expression levels of IGF2 relative to the endogenous control β2-microglobulin gene given on the y-axis in two tissues examined displayed on the x-axis. Each measurement is based on triplicate measurement of crossing points. Data are expressed as fold changes in the expression relative to the control sample used as a calibrator. Expression levels in samples from the proband, daughter, and control are given by the blue, purple, and clear bars, respectively. Upper and lower limits of expression are represented by error bars.

 

   Patients and Methods
Top
 Abstract
 Introduction
 Case report
 Patients and Methods
Results
 Discussion
 References
 
Cytogenetic, molecular, and gene expression studies

To fine map the chromosomal break points, clone DNA near the region of the cytogenetic breakpoints were selected from the University of Santa Cruz Genome Browser and Ensembl human genome databases build 36.1 (Table 2Go). Clone DNA was labeled with biotin-16-deoxyuridine 5-triphosphate (Roche, Mannheim, Germany) or digoxigenin-11-deoxyuridine 5-triphosphate (Roche) by nick translation. Biotin-labeled probes were detected using Avidin-FITC (Vector Laboratories, Burlingame, CA), and digoxigenin-labeled probes with sheep antidigoxigenin-tetramethylrhodamine isothiocyanate (Roche). To ascertain whether the translocation was truly balanced, a high-density array-comparative genomic hybridization analysis was performed using a customised constitutional Agilent 4X44 K oligo array platform (http://www.ngrl.org.uk/wessex/array.htm). Parental origin of the balanced translocation in the proband (II-1) was investigated by analyzing informative microsatellites near the 11p break point (Fig. 2Go).


Figure 4
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  		FIG. 4.
 
To exclude an associated gene mutation, the coding regions of exons 7, 8, and 9 of IGF2 were amplified from genomic DNA by PCR with primers listed in online supplementary Table 1, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://jcem.endojournals.org, and sequenced. The methylation status at the differentially methylated region 2 kb upstream of the H19 gene was determined using the H19 assay (10), with single-tube methylation-specific PCR of bisulfate-modified DNA.

Cultures of lymphoblastoid cells (from the proband (II-1), her daughter (III-4), and a control subject) and fibroblasts (from the proband and a control subject) were established. Total RNA was prepared using the Perfect RNA minikit (Eppendorf, Hamburg, Germany). Deoxyribonuclease-treated RNA was reverse transcribed using the Thermoscript RT-PCR system (Invitrogen, Paisley, UK) to yield cDNA. Real-time PCR assays for cDNA from IGF2 and H19 and the ubiquitously expressed β2-microglobulin gene were obtained from Applied Biosystems (Foster City, CA). Real-time PCRs to determine β2-microglobulin and IGF2 expression levels were carried out using ABI Prism 7000 (Applied Biosystems).

Endocrine studies for growth and diabetes

Serum concentrations of IGF-I, IGF-II and IGF binding protein (IGFBP)-3 levels were measured using double-antibody RIAs (11), and abnormal molecular forms of IGF-II were assessed using Western immunoblotting of serum. GH was evaluated by insulin tolerance test. β-Cell function was calculated from fasting insulin and glucose values using the homeostasis model assessment index (HOMAB) through the computer model version 2.2 (12).

Human leukocyte antigen (HLA) typing was conducted by PCR-restriction fragment length polymorphism (13). The patient and four nondiabetic control subjects (matched for age, sex, and body mass index) were studied with a two-step hyperinsulinemic-euglycemic clamp (step 1, 0.3 mU/kg·min; step 2, 1.5 mU/kg·min) to evaluate insulin sensitivity, using [6,6-2H2] glucose as a tracer (14). Endogenous glucose appearance rate (Ra) and glucose disposal rate (Rd) were calculated as previously described (15). Abdominal magnetic resonance imaging was performed using a 1.5 Tesla scanner (Avanto; Siemens Medical, Erlangen, Germany).

These studies were approved by the regional ethics committee and informed patient consent was obtained.


   Results
Top
 Abstract
 Introduction
 Case report
 Patients and Methods
 Results
Discussion
 References
 
Cytogenetic, molecular, and gene expression studies

The 11p15.5 break point mapped to a 60-kbregion (marked by flanking fosmids WI2–1875E5 and WI2–1660M14) about 184 kb upstream of the IGF2 gene (Fig. 3Go, A and B and Table 2Go). This region is the site of the nonskeletal muscle mesodermal-specific enhancers of IGF2 (16). The 1p36.22 break point mapped to a 183.3-kb gene-poor region 12.8 Mb from chromosome 1pter (Table 2Go), within the bacterial artificial chromosome (BAC) RP11-450I1. This BAC contains eight genes from the preferentially expressed antigen in melanoma family (PRAMEF12, PRAMEF1, PRAMEF11, PRAMEF2, PRAMEF4, PRAMEF10, PRAMEF7, PRAMEF6) and the heterogeneous nuclear ribonucleoprotein C-like 1 gene (HNRPCL1). No significant copy number changes were observed on oligo array-comparative genomic hybridization, indicating the translocation was balanced at the resolution used. Karyotyping of the patient (II-1) and her first child (III-4) showed the same balanced translocation t(1,11)(p36.22;p15.5). The proband’s second child (III-5) and mother (I-1) had a normal karyotype. Her father (I-2) was not available for investigation, but microsatellite analysis established that the translocation was not maternally derived (Fig. 2Go).


Figure 3
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  		FIG. 3. Clinical studies composite. A, Proband aged 12 months. B, Early growth of proband (solid black line) and daughter (dotted black line). C, Proband’s axial T1 weighted gradient echo image with fat suppression (repetition time 25, echo time 2.47) at the level of the umbilicus showing excess sc fat measuring 255 cm2 (reference mean 107 cm2, SD 60 cm2) (17 ).

 
No mutations were found in the three expressed exons of IGF2 gene in the proband. Methylation of H19 differentially methylated region was normal in both the proband (II-1) and her daughter (III-4). IGF2 expression by the proband’s fibroblasts was normal, but expression by her lymphoblasts was reduced (Fig. 3CGo). The proband’s daughter (III-4) had normal IGF2 expression in her lymphoblasts (Fig. 3CGo).

Endocrine studies for growth and diabetes

The patient had normal GH response to insulin-induced hypoglycemia. Serum concentrations of IGF-I, IGF-II, and IGFBP-3 were normal (Table 3Go) as they were in her first child (III-4). No abnormal molecular weight forms of IGF-II were detected. She had significant C-peptide but reduced HOMAB (–2 SDS) (Table 3Go). Glutamate acid decarboxylase and IA2 autoantibodies were not detected, and the HLA profile (HLA-DQA: 0101/2, 0101/2; HLA-DQB: 0501, 0604; HLA-DR: non-DR3 or DR4) was not characteristic of type 1 diabetes susceptibility phenotype. The euglycemic hyperinsulinemic clamp demonstrated the presence of marked peripheral and hepatic insulin resistance (Table 3Go). Magnetic resonance imaging showed structurally normal breasts, normal pancreatic volume (643 cm3), but increased abdominal sc fat 255 cm2 [+2.5 SDS (17), Fig. 1CGo].


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  		TABLE 3. Laboratory studies

 

   Discussion
Top
 Abstract
 Introduction
 Case report
 Patients and Methods
 Results
 Discussion
References
 
Our patient had a paternally derived balanced chromosomal translocation that disrupted the regulatory regions of the predominantly paternally expressed IGF2 gene. This is likely to have impacted most during fetal development by reducing IGF2 expression in certain mesodermal tissues and the placenta, resulting in her phenotype of extreme intrauterine growth retardation (birth weight –5.4 SDS) but less retardation of postnatal growth (adult weight –1.9 SDS, height –3 SDS) despite early puberty, indicating greater impact on prenatal than postnatal growth. The reduction in her final height is likely to be due to the small role of IGF-II in postnatal growth. In keeping with this, overexpression of IGF2 in patients with BWS results in fetal overgrowth (8) and tall stature (8, 18), whereas reduced expression of IGF2 from variable loss of paternal allele methylation in SRS patients results in fetal growth retardation (9) and short stature. Our case contrasts with conditions resulting from deletions or mutations in IGF1, GH, or their receptors, which are characterized by markedly low postnatal growth velocity (19, 20, 21, 22, 23).

The patient’s first child (III-4) inherited the identical translocation but had normal intrauterine growth, presumably because her normal paternally derived allele was expressed. These results are consistent with genomic imprinting and maternal silencing of IGF2 in man. In mouse, paternal (but not maternal) IGF2 knockout (24) and placental-specific, paternal igf2 knockout mice (2) both have markedly reduced intrauterine growth.

Expression of the human IGF2 gene on chromosome 11 is controlled grossly at the genomic level and more finely at the posttranscriptional level through multiple promoter-specific types of IGF-2 mRNA in different tissues (6, 25). Genomic control of IGF2 gene expression occurs through parental imprinting and the action of different enhancers that lie telomeric to the gene. Parental imprinting of IGF2 is complex and includes several sites of differential methylation both within and outside the paternally derived IGF2 gene (5, 26). The enhancers of the IGF2 gene are tissue specific: endoderm-specific enhancers are located +163 kb telomeric of IGF2; skeletal muscle mesoderm-specific enhancers at +178 kb; and other mesoderm-specific enhancers between +188 and +273 kb (Fig. 2BGo) (16). Our patient’s chromosome 11 translocation break point located at +184 kb (maximum limits between +157 and +242 kb) would thus separate her paternally derived IGF2 gene from at least some of its mesodermal-specific enhancers and is likely to have resulted in reduced mesodermal tissue expression of IGF2. In support of this hypothesis IGF2 expression was reduced in her mesoderm-derived lymphoblast cells, whereas it was normal in mixed mesoderm/ectoderm-derived skin fibroblasts (27). The location of the human placental IGF2 enhancers is unknown and may be distal to our patient’s break point, contributing to her low birth weight.

Our patient had early-onset diabetes of unusual phenotype. She had low body mass index and eventually required insulin treatment, but there were no laboratory features (C-peptide present, HLA not high risk, negative glutamate acid decarboxylase antibodies) of type 1 diabetes. Her diabetes was unusual for type 2 diabetes because she was diagnosed at 21 yr with a body mass index of 21.1 kg/m2. When type 2 diabetes occurs at this young age, it is almost invariably in very obese subjects with a strong genetic predisposition either racial or familial or both. Our patient is slim, European Caucasian, and has no family history of diabetes.

Our patient’s diabetes resulted from both insulin resistance and β-cell dysfunction. A fascinating feature was markedly excess sc body fat, having a normal body mass index and waist measurement. This was associated with marked hepatic and peripheral insulin resistance demonstrated by the clamp study, which was greater than the insulin resistance seen in obese type 2 diabetic subjects (Table 3Go). Because insulin production was reduced relative to the hyperglycemia (as shown by C peptide and HOMAB measurement) in addition to the insulin resistance, there is also a relative failure of insulin secretion. Pancreatic size was normal but assessment of β-cell mass is not possible. In the diabetes-prone GK rat, hepatic and pancreatic IGF2 expression is reduced and fetuses have a severely reduced β-cell mass (28). Conversely, increased expression of IGF2 under the control of the rat insulin promoter in β-cells of transgenic mice led to β-cell hyperplasia (29). Genetic defects in the IGF2 imprinted region have also been implicated in human disorders of glucose regulation: BWS includes neonatal hypoglycemia (8), whereas maternal duplication of the 11p15.5 region has been associated with early adult-onset diabetes, precocious puberty, and truncal obesity (10). In our patient local IGF2 underexpression has probably led to both insulin resistance through altered fat distribution and also β-cell failure, which may be either secondary to the insulin resistance or a direct pancreatic effect.

The studies of IGF-II polymorphisms and obesity have been conflicting, with only a few older studies showing an association (30, 31, 32), which was not confirmed in a larger study (33). Interestingly, IGFBP2 polymorphisms have recently been shown to predispose to type 2 diabetes in large genomewide association studies and replication cohorts (34).

Low circulating levels of IGF-II have been found to be associated with weight gain and obesity (35); however, this has not been confirmed by all studies, particularly in women (36). Serum IGF-II concentrations are predominantly liver derived and may not represent the key biological determinants of IGF-II. IGF-II concentrations are normal in both SRS and BWS, which both show altered growth (37, 38), because of biallelic expression of IGF2 in the postnatal liver. Hence, it is not surprising that serum levels of IGF-II in our patient were also normal.

Our patient had other phenotypic features that remain unexplained and have not been observed in IGF2 knockout mice, including complete lactational failure (in two pregnancies). IGF2 is known to be important in breast development, inducing ductal branching and alveolar development in the mouse mammary gland (39, 40), but female igf2 knockout mice breed normally and nurse their pups (1).

In summary, we have described a woman with a balanced translocation that disrupted access of her paternally derived IGF2 gene to its telomeric mesodermal enhancers. Her distinctive phenotype included severe intrauterine growth retardation, atypical diabetes, and lactation failure. Despite inheriting the identical translocation, her daughter had normal intrauterine growth due to imprinting of IGF2 in humans.


   Acknowledgments
 
The authors thank the patient and her family. We gratefully acknowledge Simon Thomas (Wessex Regional Genetics Laboratory, Salisbury, UK) for performing the H19 methylation assay, microsatellite analysis, and helpful discussions; Paul Oei (Department of Cytogenetics, LabPlus, Auckland, New Zealand) for the initial cytogenetic studies; Jinny Willis, (Lipid and Diabetes Research, Christchurch Hospital, Christchurch, New Zealand) for the HLA typing; Anthony Doyle for the magnetic resonance imaging interpretation; and Jo Batt (Wolfson Centre for Translational Research, University of Surrey, Surrey, UK) for measuring glucose enrichment and nonesterified fatty acid concentrations in the clamp samples. We also thank Wolf Reik (Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, UK) and Ian Morison (Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand) for helpful discussions. We are thankful to the Sanger Institute for kindly providing the clones used for fine mapping in this study.


   Footnotes
 
This work was supported by Diabetes UK, Wellcome Trust, Auckland Medical Research Foundation, and NovoNordisk research awards.

Disclosure Statement: All authors have nothing to declare.

First Published Online August 26, 2008

Abbreviations: BAC, Bacterial artificial chromosome; BWS, Beckwith-Wiedemann syndrome; HLA, human leukocyte antigen; HOMAB, homeostasis model assessment index for β-cell function; IGFBP, IGF binding protein; Ra, glucose appearance rate; Rd, glucose disposal rate; SDS, SD score; SRS, Silver-Russell syndrome.

Received April 15, 2008.

Accepted August 15, 2008.


   References
Top
 Abstract
 Introduction
 Case report
 Patients and Methods
 Results
 Discussion
 References
 

  1. DeChiara TM, Efstratiadis A, Robertson EJ 1990 A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345:78–80[CrossRef][Medline]
  2. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith AC, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W 2002 Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417:945–948[CrossRef][Medline]
  3. Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC 1999 A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol 19:1262–1270[Abstract/Free Full Text]
  4. Pedersen SK, Christiansen J, Hansen TO, Larsen MR, Nielsen FC 2002 Human insulin-like growth factor II leader 2 mediates internal initiation of translation. Biochem J 363:37–44[CrossRef][Medline]
  5. Murrell A, Heeson S, Reik W 2004 Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Nat Genet 36:889–893[CrossRef][Medline]
  6. Vu TH, Hoffman A 1994 Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371:714–717[CrossRef][Medline]
  7. Ekstrom T, Cui H, Li X, Ohlsson R 1995 Promoter-specific IGF2 imprinting status and its plasticity during human liver development. Development 121:309–316[Abstract]
  8. Weksberg R, Smith A, Squire J, Sadowski PD 2003 Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 12:61–68[Abstract/Free Full Text]
  9. Gicquel C, Rosssignol S, Cabrol S, Houang M, Stenou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand A, Netchine I, Le Bouc Y 2005 Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37:1003–1007[CrossRef][Medline]
  10. Fisher A, Thomas N, Cockwell A, Stecko O, Kerr B, Temple IK, Clayton P 2002 Duplications of chromosome 11p15 of maternal origin result in a phenotype that includes growth retardation. Hum Genet 111:290–296[CrossRef][Medline]
  11. Cheetham TD, Holly JM, Baxter RC, Meadows K, Jones J, Taylor AM, Dunger DB 1998 The effects of recombinant human IGF-I administration on concentrations of acid labile subunit, IGF binding protein-3, IGF-I, IGF-II and proteolysis of IGF binding protein-3 in adolescents with insulin-dependent diabetes mellitus. J Endocrinol 157:81–87[Abstract]
  12. Levy JC, Matthews DR, Hermans MP 1998 Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21:2191–2192[Medline]
  13. Teutsch SM, Bennetts BH, Castle M, Hibbins M, Heard RN, Stewart GJ 1996 HLA-DQA1 and -DQB1 genotyping by PCR-RFLP, heteroduplex and homoduplex analysis. Eur J Immunogenet 23:107–120[CrossRef][Medline]
  14. DeFronzo RA, Simonson D, Ferrannini E 1982 Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23:313–319[Medline]
  15. Brackenridge A, Pearson ER, Shojaee-Moradie F, Hattersley AT, Russell-Jones D, Umpleby AM 2006 Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1β and -1{alpha} mutations. Diabetes 55:405–411[Abstract/Free Full Text]
  16. Gabory A, Ripoche MA, Yoshimizu T, Dandolo L 2006 The H19 gene: regulation and function of a non-coding RNA. Cytogenet Genome Res 113:188–193[CrossRef][Medline]
  17. Gomi T, Kawawa Y, Nagamoto M, Terada H, Kohda E 2005 Measurement of visceral fat/subcutaneous fat ratio by 0.3 tesla MRI. Radiat Med 23:584–587[Medline]
  18. Murrell A, Heeson S, Cooper WN, Douglas E, Apostolidou S, Moore GE, Maher ER, Reik W 2004 An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Mol Genet 13:247–255[Abstract/Free Full Text]
  19. Binder G, Keller E, Mix M, Massa GG, Stokvis-Brantsma WH, Wit JM, Ranke MB 2001 Isolated GH deficiency with dominant inheritance: new mutations, new insights. J Clin Endocrinol Metab 86:3877–3881[Abstract/Free Full Text]
  20. Savage MO, Blum WF, Ranke MB, Postel-Vinay MC, Cotterill AM, Hall K, Chatelain PG, Preece MA, Rosenfeld RG 1993 Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 77:1465–1471[Abstract]
  21. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363–1367[Free Full Text]
  22. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211–2222[Abstract/Free Full Text]
  23. Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA, van Thiel SW, Sluimers CA, Bax JJ, de Laat JA, Breuning MB, Romijn JA, Wit JM 2005 Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 90:2855–2864[Abstract/Free Full Text]
  24. DeChiara T, Roberston E, Efstratiadis A 1991 Parental imprinting of the mouse insulin-like growth factor gene. Cell 64:849–859[CrossRef][Medline]
  25. Wu H, Squire J, Song Q, Weksberg R 1997 Promoter-dependent tissue-specific expressive nature of imprinting gene, insulin-like growth factor II, in human tissues. Biochem Biophys Res Commun 233:221–226[CrossRef][Medline]
  26. Murrell A, Heeson S, Bowden L, Constancia M, Dean W, Kelsey G, Reik W 2001 An intragenic methylated region in the imprinted Igf2 gene augments transcription. EMBO Rep 2:1101–1106[CrossRef][Medline]
  27. Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO 2002 Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA 99:12877–12882[Abstract/Free Full Text]
  28. Serradas P, Goya L, Lacorne M, Gangnerau M, Ramos S, Alvarez C, Pascual-Leone A, Portha B 2002 Fetal insulin-like growth factor-2 production is impaired in the GK rat model of type 2 diabetes. Diabetes 51:392–397[Abstract/Free Full Text]
  29. Devedjian JC, George M, Casellas A, Pujol A, Visa J, Pelegrin M, Gros L, Bosch F 2000 Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes. J Clin Invest 105:731–740[Medline]
  30. O'Dell SD, Bujac SR, Miller GJ, Day IN 1999 Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity. Eur J Hum Genet 7:821–827[CrossRef][Medline]
  31. Gaunt TR, Cooper JA, Miller GJ, Day IN, O'Dell SD 2001 Positive associations between single nucleotide polymorphisms in the IGF2 gene region and body mass index in adult males. Hum Mol Genet 10:1491–1501[Abstract/Free Full Text]
  32. O'Dell SD, Miller GJ, Cooper JA, Hindmarsh PC, Pringle PJ, Ford H, Humphries SE, Day IN 1997 Apal polymorphism in insulin-like growth factor II (IGF2) gene and weight in middle-aged males. Int J Obes Relat Metab Disord 21:822–825[CrossRef][Medline]
  33. Heude B, Ong KK, Luben R, Wareham NJ, Sandhu MS 2007 Study of association between common variation in the insulin-like growth factor 2 gene and indices of obesity and body size in middle-aged men and women. J Clin Endocrinol Metab 92:2734–2738[Abstract/Free Full Text]
  34. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, McCarthy MI, Hattersley AT 2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341[Abstract/Free Full Text]
  35. Sandhu MS, Gibson JM, Heald AH, Dunger DB, Wareham NJ 2003 Low circulating IGF-II concentrations predict weight gain and obesity in humans. Diabetes 52:1403–1408[Abstract/Free Full Text]
  36. Rodriguez S, Gaunt TR, Dennison E, Chen XH, Syddall HE, Phillips DI, Cooper C, Day IN 2006 Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes. Eur J Hum Genet 14:109–116[Medline]
  37. Binder G, Seidel AK, Weber K, Haase M, Wollmann HA, Ranke MB, Eggermann T 2006 IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus. J Clin Endocrinol Metab 91:4709–4712[Abstract/Free Full Text]
  38. Schneid H, Vazquez M, Vacher M, Gourmelen S, Cabrol S, Le Bouc S 1997 The Beckwith-Wiedemann syndrome phenotype and the risk of cancer. Med Pediatr Oncol 28:411–415[CrossRef][Medline]
  39. Hovey RC, Harris J, Hadsell DL, Lee AV, Ormandy CJ, Vonderhaar BK 2003 Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol 17:460–471[Abstract/Free Full Text]
  40. Brisken C, Ayyannan A, Nguyen C, Heineman A, Reinhardt F, Tan J, Dey SK, Dotto GP, Weinberg RA 2002 IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev Cell 3:877–887[CrossRef][Medline]
  41. Hwa V, Haeusler G, Pratt KL, Little BM, Frisch H, Koller D, Rosenfeld RG 2006 Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab 91:1826–1831[Abstract/Free Full Text]
  42. Domene HM, Bengolea SV, Martinez AS, Ropelato MG, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG 2004 Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 350:570–577[Free Full Text]
  43. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG 2003 Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 349:1139–1147[Free Full Text]
  44. Vidarsdottir S, Walenkamp MJ, Pereira AM, Karperien M, van Doorn J, van Duyvenvoorde HA, White S, Breuning MH, Roelfsema F, Kruithof MF, van Dissel J, Janssen R, Wit JM, Romijn JA 2006 Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab 91:3482–3485[Abstract/Free Full Text]



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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
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