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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two sibs with early onset diabetes and epiphysed dysplasia (Wolcott-Rallison syndrome) are described. The epiphyseal changes were radiologically apparent at 6 months of age in one of them, and both developed insulin dependent diabetes in the first few weeks of life. The clinical and radiological features of this syndrome are reviewed.
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PMID:Wolcott-Rallison syndrome. 755 Nov 59

Wolcott-Rallison syndrome is a rare autosomal recessive condition first described in 1972. It is characterised by diabetes mellitus which arises in early infancy and multiple epiphyseal dysplasia. We describe an affected girl who had recurrent episodes of hepatic failure for which no obvious cause was found. Post-mortem examination revealed abnormal pancreatic histology and congenital abnormalities of the central nervous and cardio-respiratory systems which have not been previously described in this condition. She also demonstrated a deletion at 15q 11-12 in 65% of her cells.
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PMID:Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q 11-12. 873 81

Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by diabetes mellitus arising in early infancy and multiple epiphyseal dysplasia. To date, nine cases have been described in the world literature. We report an affected girl who died at the age of 4 years and on whom a full autopsy was performed. In addition to neonatal diabetes mellitus and epiphyseal dysplasia, this child had mental retardation and recurrent episodes of self-limiting hepatic failure. Autopsy revealed severe pancreatic hypoplasia and markedly abnormal pancreatic histology, while histology of the bone was consistent with epiphyseal dysplasia. There was laryngeal stenosis and pulmonary hypoplasia. The heart was enlarged with mitral value dysplasia and stenosis, left atrial dilatation, left ventricular hypertrophy, and endocardial fibroelastosis. Examination of the central nervous system showed arrhinencephaly and cerebellar cortical dysplasia. The liver showed minor histological abnormalities but no features were present to account for the recurrent hepatic failure. In addition to Wolcott-Rallison syndrome this child had a deletion at 15q11-12 in 65% of her cells.
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PMID:Autopsy findings in the Wolcott-Rallison syndrome. 918 26

Neonatal diabetes mellitus is a rare condition, the causes of which are mostly unknown. One well defined though very rare entity is the autosomal recessive Wolcott-Rallison syndrome, in which permanent neonatal diabetes, osteopenia, and epiphyseal dysplasia occur. Only five previous families have been reported, and here we describe the second in which parental consanguinity was present. The proband was born to first cousin parents and died at 2 years from the sequelae of poorly controlled diabetes. To test the hypothesis that mutation of PAX4, required in the mouse for pancreatic islet beta cell development, might cause WRS, the structure of the human PAX4 gene was deduced and DNA from two unrelated WRS patients sequenced. No PAX4 mutation was present, though the entire coding region was sequenced in both patients. It therefore appears unlikely that PAX4 is involved in the aetiology of Wolcott-Rallison syndrome, though it remains a good candidate for other forms of neonatal diabetes mellitus.
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PMID:Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome. 959 21

Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.
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PMID:EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. 1093 83

Phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2 alpha) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2 alpha (eIF-2 alpha[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2 alpha. Among the four eIF-2 alpha kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2 alpha[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk(-/-) mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk(-/-) mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
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PMID:The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. 1199 20

Wolcott-Rallison syndrome (WRS) is an autosomal recessive disorder characterized by neonatal or early infancy type 1 diabetes, epiphyseal dysplasia, and growth retardation. Mutations in the EIF2AK3 gene, encoding the eukaryotic initiation factor 2alpha-kinase 3 (EIF2AK3), have been found in WRS patients. Here we describe a girl who came to our attention at 2 months of age with severe hypertonic dehydration and diabetic ketoacidosis. A diagnosis of type 1 diabetes was made and insulin treatment initiated. Growth retardation and microcephaly were also present. Anti-islet cell autoantibodies were negative, and mitochondrial diabetes was excluded. Imaging revealed a hypoplastic pancreas and typical signs of spondylo-epiphyseal dysplasia. The diagnosis of WRS was therefore made at age 5 years. Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense serine 877 proline mutation. The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha). This is the first case in which the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level. Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans, and we suggest EIF2AK3 as a possible target for therapeutic intervention in diabetes.
Diabetes 2002 Jul
PMID:Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. 1208 64

The early steps of insulin biosynthesis occur in the endoplasmic reticulum (ER), and the beta-cell has a highly developed and active ER. All cells regulate the capacity of their ER to fold and process client proteins and they adapt to an imbalance between client protein load and folding capacity (so-called ER stress). Mutations affecting the ER stress-activated pancreatic ER kinase (PERK) and its downstream effector, the translation initiation complex eukaryotic initiation factor 2 (eIF2), have a profound impact on islet cell development, function, and survival. PERK mutations are associated with the Wolcott-Rallison syndrome of infantile diabetes and mutations that prevent the alpha-subunit of eIF2 from being phosphorylated by PERK, block beta-cell development, and impair gluconeogenesis. We will review this and other rare forms of clinical and experimental diabetes and consider the role of ER stress in the development of more common forms of the disease.
Diabetes 2002 Dec
PMID:Endoplasmic reticulum stress and the development of diabetes: a review. 1247 90

Type 2 diabetes is a polygenic disorder characterized by multiple biochemical defects including transcriptional, translational, and posttranslational abnormalities. Although major progress has been made in elucidation of factors at the transcriptional and posttranslational levels, defects at the translational level remain elusive. Mutation of a kinase that regulates translation initiation has been implicated in the etiology of a monogenic form of diabetes known as Wolcott-Rallison syndrome. Characterization of mice rendered deficient in eukaryotic initiation factors has provided model systems to study the involvement of translation in regulating insulin synthesis and secretion, hepatic function, peripheral insulin resistance, and diabetic complications. Recent progress in the understanding of endoplasmic reticulum overload by unfolded proteins has begun to uncover mechanisms leading to pancreatic beta-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of beta-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.
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PMID:When translation meets metabolism: multiple links to diabetes. 1258 11

Congenic BB.SHR (D4Got41-Npy-Tacr1; BB.4S) rats develop an incomplete metabolic syndrome with obesity, hyperleptinemia, and dyslipidemia compared with their progenitor strain, the diabetes-prone BB/OK rat. To narrow down the underlying gene(s), two subcongenic BB.SHR rat lines, briefly termed BB.4Sa and BB.4Sb, were generated. Male BB.4S (n = 20), BB.4Sa (n = 24), and BB.4Sb (n = 26) were longitudinally characterized for facets of the metabolic syndrome and analyzed for expression of genes located in the region of interest in liver and blood. Body weight gain was comparable, serum triglycerides and leptin were significantly increased, and total cholesterol and HDL-cholesterol ratio were decreased in BB.4S compared with both subcongenics. Serum insulin was significantly higher in BB.4S and BB.4Sa than in BB.4Sb. The adiposity index showed a graduated decrease from BB.6S to BB.4Sb. Obvious differences in relative expression were found in 6 of 10 genes in liver and in 2 of 9 genes in blood. Only one gene, the eukaryotic translation initiation factor 2alpha kinase 3 (Eif2ak3 also called Perk or Pek), was significantly less expressed in liver and in blood of both subcongenic BB.4Sa and BB.4Sb compared with their "parental" BB.4S rats. Based on the phenotype and genotype in BB.4S and its subcongenic derivatives, the most important region on chromosome 4 can be said to lie between D4Got72 and Tacr1. Eif2ak3 is mapped in this region. Considering the function of Eif2ak3, it may be a candidate gene for the development of glucose intolerance found in both subcongenics but not in BB.4S. Allelic variants between BB/OK and SHR could influence Eif2ak3 function, possibly leading not only to glucose intolerance but also to the disturbances in hepatic and renal function found in human Wolcott-Rallison syndrome.
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PMID:Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome. 1517 49


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