Gene expression in human cells with mutant insulin receptors

Melis, Roberta; Pruett, Paul B; Wang, Yuhuan; Longo, Nicola

doi:10.1016/s0006-291x(03)01293-2

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…Only in some cases were genes regulated in more than one cell type (Fig. 3), but the general pattern of regulated functional clusters was similar: most genes were Consistent with other studies [24,28], a large number of genes assigned to metabolism were differentially expressed (Fig. 2).…”

Section: Discussionsupporting

confidence: 87%

“…We identified 371 insulin-responsive genes that were specifically regulated in one compartment of the placenta. Some of the genes had also been identified in other microarray studies, which used different cell models, stimulation and analysis modalities [24][25][26][27][28], or by other methods [9,10], thus representing a robust insulin response common to many cell types.…”

Section: Discussionmentioning

confidence: 99%

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Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

et al. 2005

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Aims/hypothesis: The human placenta is a complex organ situated at the interface between mother and foetus that separates maternal from foetal blood. The placental surfaces exposed to the two bloodstreams are different, i.e. trophoblasts and endothelial cells are in contact with the maternal and foetal circulation, respectively. Both cell types produce high insulin receptor levels. The aim of the present study was to test the hypothesis that spatiotemporal changes in insulin receptor expression in trophoblasts from first trimester to the endothelium at term shift the control of insulin-dependent processes from mother to foetus. Methods: Global microarray analysis of primary trophoblasts from first trimester and term human placentas and endothelial cells from term human placentas cultured under hyperinsulinaemic and control conditions identified different sets of regulated genes in trophoblasts and endothelial cells. Results: Insulin effects on placental gene expression underwent developmental changes from trophoblasts in the first trimester to endothelial cells at term that were paralleled by changes in levels of activated insulin receptors. The changes in gene regulation were both quantitative (i.e. magnitude of effect) and qualitative (i.e. specific genes affected and direction of regulation). Conclusions/interpretation: This spatio-temporal shift in insulin sensitivity throughout pregnancy allows maternal and foetal insulin to regulate different processes within the placenta at different gestational stages, facilitated by compartmentalisation of the insulin response. Thus, by altering the levels and function of insulin receptors in space and time, control of insulin-dependent processes in the human placenta will change from mother to foetus throughout gestation. This will be of particular interest in conditions associated with altered maternal or foetal insulin levels, i.e. diabetes mellitus or intrauterine growth restriction.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

et al. 2005

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“…The first patient, NY1, with clinically-confirmed Leprechaunism [6], [22], had a homozygous G to T variation at nucleotide 451 converting Glu 151 to a premature stop codon (c.451G > T,p.Glu151term). The second patient, 452, was a female infant with symptoms including repeated transient hypoglycemic episodes, prominent female genitalia, marked hirsutism, breast hyperplasia, loose and pachydermatous skin, decreased adipose tissue, acanthosis nigricans, and abdominal distention [7].…”

Section: Resultsmentioning

confidence: 99%

Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene

Ardon

Procter

Tvrdik

et al. 2014

Molecular Genetics and Metabolism Reports

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Mutations in the insulin receptor gene cause the inherited insulin resistant syndromes Leprechaunism and Rabson–Mendenhall syndrome. These recessive conditions are characterized by intrauterine and post-natal growth restrictions, dysmorphic features, altered glucose homeostasis, and early demise. The insulin receptor gene (INSR) maps to the short arm of chromosome 19 and is composed of 22 exons. Here we optimize the conditions for sequencing this gene and report novel mutations in patients with severe insulin resistance.MethodsPCR amplification of the 22 coding exons of the INSR gene was performed using M13-tailed primers. Bidirectional DNA sequencing was performed with BigDye Terminator chemistry and M13 primers and the product was analyzed on the ABI 3100 genetic analyzer. Data analysis was performed using Mutation Surveyor software comparing the sequence to a reference INSR sequence (Genbank NC_000019).ResultsWe sequenced four patients with Leprechaunism or Rabson–Mendenhall syndromes as well as seven samples from normal individuals and confirmed previously identified mutations in the affected patients. Three of the four mutations identified in this group caused premature insertion of a stop codon. In addition, the INSR gene was sequenced in 14 clinical samples from patients with suspected insulin resistance and one novel mutation was found in an infant with a suspected diagnosis of Leprechaunism.DiscussionLeprechaunism and Rabson–Mendenhall syndrome are very rare and difficult to diagnose. Diagnosis is currently based mostly on clinical criteria. Clinical availability of DNA sequencing can provide an objective way of confirming or excluding the diagnosis.

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“…52 The latest research in these syndromes has shown, by gene expression studies, significant alterations in the expression of genes encoding growth factors (including insulin-like growth factors) and apoptotic factors in patients with Donohue syndrome. 53 Further work in this area may help link the contributions of insulin resistance and loss of b cell mass in diabetes pathology.…”

Section: Insulin Resistancementioning

confidence: 99%

Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and cell failure

Porter

2005

Journal of Medical Genetics

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Gene expression in human cells with mutant insulin receptors

Cited by 6 publications

References 19 publications

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene

Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and cell failure

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