Wolcott‐Rallison syndrome in two siblings with isolated central hypothyroidism

Bin-Abbas, Bassam; Al-Mulhim, Abdulmohsen A.; Al-Ashwal, Abdullah A.

doi:10.1002/ajmg.10495

Cited by 39 publications

(38 citation statements)

References 11 publications

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“…A total of 12 families (18 patients with WRS) were studied, including the two original families that we previously reported (4), and other previously reported cases from Germany (6), Mauritania/France (12), and Saudi Arabia (13)(14)(15). Six other families from Quebec, Iran/Belgium, Pakistan/U.K., Slovakia, Italy, and Turkey have not been previously reported.…”

Section: Methodsmentioning

confidence: 99%

Wolcott-Rallison Syndrome

et al. 2004

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Section: Methodsmentioning

confidence: 99%

Wolcott-Rallison Syndrome

et al. 2004

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“…In this inherited defect of the UPR, children develop skeletal abnormalities, infantile diabetes, and interestingly there are reports of renal insufficiency (7,38), including proteinuria. The proteinuria could indicate podocyte or tubular epithelial cell dysfunction, although prerenal azotemia also plays a role in renal disease.…”

Section: Modulators Of Er Stressmentioning

confidence: 96%

The endoplasmic reticulum stress response and diabetic kidney disease

Cunard

Sharma

2011

American Journal of Physiology-Renal Physiology

121

112

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The endoplasmic reticulum (ER) folds and modifies proteins; however, during conditions of cellular stress, unfolded proteins accumulate in the ER and activate the unfolded protein response (UPR). The UPR, also referred to as the ER stress response, activates three distinct signaling cascades that are designed to globally reduce transcription and translation. The three major arms of the mammalian UPR include 1) protein kinase RNA (PKR)-like ER kinase (PERK), 2) inositol-requiring protein-1 (IRE1α), and 3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and IRE1α cascades transcriptionally upregulate ER chaperone genes that promote proper folding and ER-associated degradation (ERAD) of proteins. This integrated response in turn allows the folding machinery of the ER to catch up with the backlog of unfolded proteins. The ER stress response plays a role in a number of pathophysiological processes, including pancreatic β-cell failure and apoptosis. The goals of the current review are to familiarize investigators with cellular and tissue activation of this response in the rodent and human diabetic kidney. Additionally, we will review therapeutic modulators of the ER stress response and discuss their efficacy in models of diabetic kidney disease. The ER stress response has both protective and deleterious features. A better understanding of the molecular pathways regulated during this process in a cell- and disease-specific manner could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.

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“…WRS patients have characteristic diseases related to many secretory tissues. The affected cell types include pancreatic islet beta cells, leading to early onset of diabetes, osteoblasts contributing to epiphyseal dysplasia, pancreatic acinar cells leading to digestive disorders, and thyroid cells promoting hypothyroidism (6,8,58). It is thought that normal developmental processes occurring after birth contribute to cellular ER stress that is magnified in tissues with extensive secretory organelles.…”

Section: Phosphorylation Of Eif2␣ Is Required To Activate Nf-b In Resmentioning

confidence: 99%

“…Loss of PEK (EIF2AK3) in humans leads to Wolcott-Rallison syndrome (WRS), a disorder involving neonatal insulin-dependent diabetes resulting from a characteristic destruction of pancreatic islet beta cells (11). WRS patients do not display autoantibodies characteristic of type 1 diabetes, and they also suffer from epiphyseal dysplasia, osteoporosis, growth retardation, recurrent hepatitis, and isolated central hypothyroidism (6,8,58). PEK Ϫ/Ϫ mice display many of these phenotypes and succumb to complications related to hyperglycemia within several weeks of birth (21,72).…”

mentioning

confidence: 99%

Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses

Jiang

Wek

McGrath

et al. 2003

Molecular and Cellular Biology

391

339

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Nuclear factor B (NF-B) serves to coordinate the transcription of genes in response to diverse environmental stresses. In this report we show that phosphorylation of the ␣ subunit of eukaryotic initiation factor 2 (eIF2) is fundamental to the process by which many stress signals activate NF-B. Phosphorylation of this translation factor is carried out by a family of protein kinases that each respond to distinct stress conditions. During impaired protein folding and assembly in the endoplasmic reticulum (ER), phosphorylation of eIF2␣ by PEK (Perk or EIF2AK3) is essential for induction of NF-B transcriptional activity. The mechanism by which NF-B is activated during ER stress entails the release, but not the degradation, of the inhibitory protein IB. During amino acid deprivation, phosphorylation of eIF2␣ by GCN2 (EIF2AK4) signals the activation of NF-B. Furthermore, inhibition of general translation or transcription by cycloheximide and actinomycin D, respectively, elicits the eIF2␣ phosphorylation required for induction of NF-B. Together, these studies suggest that eIF2␣ kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIF␣ phosphorylation is central to activation of the NF-B. The absence of NF-B-mediated transcription and its antiapoptotic function provides an explanation for why eIF2␣ kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease.

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Wolcott‐Rallison syndrome in two siblings with isolated central hypothyroidism

Cited by 39 publications

References 11 publications

Wolcott-Rallison Syndrome

Wolcott-Rallison Syndrome

The endoplasmic reticulum stress response and diabetic kidney disease

Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses

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