Wolcott-Rallison Syndrome

Senée, Valérie; Vattem, Krishna M.; Délépine, Marc; Rainbow, Lynn A.; Haton, Céline; Lecoq, Annick; Shaw, Nick; Robert, Jean Jacques; Rooman, Raoul; Diatloff-Zito, C.; Michaud, Jacques L.; Bin-Abbas, Bassan; Taha, Doris; Zabel, Bernard; Franceschini, P; Topaloğlu, Ali Kemal; Lathrop, G.M.; Barrett, Timothy; Nicolino, Marc; Wek, Ronald C.; Julier, Cécile

doi:10.2337/diabetes.53.7.1876

Cited by 172 publications

(192 citation statements)

References 27 publications

(17 reference statements)

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“…Since the R584D mutation inactivated mouse PERK, we propose that the corresponding R587Q mutation in PERK from the patients with Wolcott-Rallison syndrome inactivates the kinase by blocking formation of a transdimer salt bridge. This notion is consistent with the inability of the human PERK-R587Q mutant to phosphorylate eIF2␣ either in vitro or in yeast cells (33). We conclude that the intermolecular salt bridge identified in PKR is also critical for the function of PERK following its oligomerization in response to ER stress.…”

Section: Volume 282 • Number 9 • March 2 2007supporting

confidence: 75%

Conserved Intermolecular Salt Bridge Required for Activation of Protein Kinases PKR, GCN2, and PERK

Dey

Cao

Sicheri

et al. 2007

Journal of Biological Chemistry

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The protein kinases PKR, GCN2, and PERK phosphorylate translation initiation factor eIF2␣ to regulate general and genespecific protein synthesis under various cellular stress conditions. Recent x-ray crystallographic structures of PKR and GCN2 revealed distinct dimeric configurations of the kinase domains. Whereas PKR kinase domains dimerized in a back-toback and parallel orientation, the GCN2 kinase domains displayed an antiparallel orientation. The dimerization interfaces on PKR and GCN2 were localized to overlapping surfaces on the N-terminal lobes of the kinase domains but utilized different intermolecular contacts. A key feature of the PKR dimerization interface is a salt bridge interaction between Arg 262 from one protomer and Asp 266 from the second protomer. Interestingly, these two residues are conserved in all eIF2␣ kinases, although in the GCN2 structure, the two residues are too remote to interact. To test the importance of this potential salt bridge interaction in PKR, GCN2, and PERK, the residues constituting the salt bridge were mutated either independently or together to residues with the opposite charge. Single mutations of the Asp (or Glu) and Arg residues blocked kinase function both in yeast cells and in vitro. However, for all three kinases, the double mutation designed to restore the salt bridge interaction with opposite polarity resulted in a functional kinase. Thus, the salt bridge interaction and dimer interface observed in the PKR structure is critical for the activity of all three eIF2␣ kinases. These results are consistent with the notion that the PKR structure represents the active state of the eIF2␣ kinase domain, whereas the GCN2 structure may represent an inactive state of the kinase.

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Section: Volume 282 • Number 9 • March 2 2007supporting

confidence: 75%

Conserved Intermolecular Salt Bridge Required for Activation of Protein Kinases PKR, GCN2, and PERK

Dey

Cao

Sicheri

et al. 2007

Journal of Biological Chemistry

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“…The previously reported mutations leading to WRS were not found. 5,9,10 Nucleotide variations were found at 11 different residues of the EIF2AK3 gene ( Figure 1 and Table 2), corresponding to nine previously reported polymorphisms and two novel SNPs found in exon 1 (position 242 G/T; Arg57Leu) and intron 6 (position 2661 A/G), respectively. Inspection of the sequences in these subjects suggest linkage disequilibrium (LD) of all SNPs apart from the 15INDEL, and that five possible haplotypes were defined by four SNPs 2, 3, 10 and 11.…”

Section: Resultsmentioning

confidence: 67%

“…The onset of diabetes in the probands of WRS families is mainly below the age of 3 months and permanent severe insulin deficiency was present in the 15 families that have been reported to date. [5][6][7][8][9][10] In those families examined, with the exception of one, 5 islet cell antibodies were not detected in the diabetic subjects and in the single case of WRS that came to autopsy the pancreas was found to be hypoplastic, with interstitial fibrosis and poor staining for insulin. 6,8 It is therefore likely that the diabetes of WRS is due to beta cell dysfunction, which in turn contributes to the aetiology of T1DM.…”

Section: Introductionmentioning

confidence: 90%

“…The WolcottRallison syndrome (WRS; MIM 226980), inherited as an autosomal recessive trait, has been classified as a rare cause of early-childhood insulin-dependent diabetes. 4,5 The syndrome is characterised by a short trunk compared to arm span, multiple epiphyseal dysplasia, bone demineralisation, multiple fractures, tooth discoloration, abnormal skin, hepatosplenomegaly and renal insufficiency, in addition to insulin-dependent diabetes. The onset of diabetes in the probands of WRS families is mainly below the age of 3 months and permanent severe insulin deficiency was present in the 15 families that have been reported to date.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations of the gene-encoding translation initiation factor 2-alpha kinase 3 (EIF2AK3) were found to account for WRS in all but one of the families published. 5 Of the 15 reported mutations, approximately two-thirds are located to the Ser/Thr protein kinase domains. 5,9,10 To further support the candidacy of the EIF2AK3 gene, 'suggestive' evidence for linkage was found between the chromosomal region (2p12), encoding this gene, and T1DM in Scandinavian families; a single-point lod score of 2.1 was reported for the marker D2S113, which is 3 0 to EIF2AK3.…”

Section: Introductionmentioning

confidence: 99%

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The EIF2AK3 gene region and type I diabetes in subjects from South India

Mohan²,

McDermott³

et al. 2004

Genes Immun

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Mutations in the EIF2AK3 gene underlie susceptibility to the Wolcott-Rallison syndrome, which is a monogenic disease associated with insulin-deficient neonatal diabetes. Furthermore, suggestive evidence of linkage between type 1 diabetes (T1DM) and the EIF2KA3 chromosomal region has been reported in Scandinavian families. We have investigated the hypothesis that polymorphic variants in and around the EIF2AK3 gene might partially account for susceptibility to T1DM in South Indian subjects. Excess transmission of the common alleles of two polymorphic markers (D2S1786 and 15INDEL, located within the gene) downstream of EIF2AK3, either singly (D2S1786, P ¼ 0.01) and 15INDEL (P ¼ 0.02) or as a combination (Po0.001), were found in 234 families with a T1DM proband. There was also a clear paternal effect for the 15INDEL marker (P ¼ 0.005) on disease susceptibility. The presence of the common allele of both markers was found in decreased frequency in the subjects with normal glucose tolerance compared to probands with T1DM (both Pp0.0001). Major common mutations of the EIF2AK3 gene in T1DM were excluded. In conclusion, this pilot study demonstrates an association between the region around the EIF2AK3 locus and T1DM susceptibility.

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