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PubMed1998

Organization of the human glucokinase regulator gene GCKR.

Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels. As a result, one form of maturity onset diabetes of the young (MODY) results from haploinsufficiency of glucokinase. In both liver and pancreatic islet, glucokinase is allosterically regulated by an inhibitory protein (glucokinase regulatory protein, GCKR). GCKR has therefore become an important gene for functional analysis in type 2 diabetes. To allow genetic assessment of any such role, we have determined the structure of the human GCKR gene. Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb. RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat. By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA. This alters amino acid residue 446 from proline, conserved in rat and Xenopus, to leucine.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A novel feature of DNA recognition: a mutant Gcn4p bZip peptide with dual DNA binding specificities dependent of half-site spacing.

Homodimeric DNA-binding proteins with relaxed half-site spacing requirements for their DNA targets have been described. As an example, the yeast transcriptional activator Gcn4p binds in vitro equally well to the AP1 site (5'A4T3G2A1C0T1'C2'A3'T4'3') and the ATF/CREB site (5'A4T3G2A1C0G0'T1'C2'A3'T4'3'), which have identical but differently spaced half-site blocks. We describe a novel feature for the bZip class of DNA-binding proteins. The N-14 mutant of a Gcn4p-derived bZip peptide shows a diametrically opposed base-pair recognition specificity depending on the half-site spacing of its DNA target: on pseudo-palindromic, AP1 site-like binding sites, guanine is required in position 2 for proper binding; in contrast, on palindromic, ATF/CREB site-like targets, position 2 must be cytosine to prevent a loss of binding. Modeling studies suggest that the different base-pair requirements on differently spaced DNA targets are due to minimal alterations of the distances between the relevant atoms of the N-14 side-chain and the corresponding target groups on the DNA. Although the N-14 peptide does not have a natural counterpart, its behavior hints at the possibility that dual binding modi dependent on half-site spacing may occur also for natural homodimeric DNA-binding proteins.

Base Sequence↗
PubMed2001

The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus.

Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha). Here, we describe the crystal structure of the HNF-1alpha dimerization domain at 1.7 A resolution and assess its structural plasticity. The crystal's low solvent content (23%, v/v) leads to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold crystallographic symmetry axis. The dimers define a novel intertwined four-helix bundle (4HB). Each protomer contains two alpha-helices separated by a sharp non-canonical turn. Dimer-related alpha-helices form anti-parallel coiled-coils, including an N-terminal "mini-zipper" complementary in structure, symmetry and surface characteristics to transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains (five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar intertwined dimer exists in solution. Comparison of structures obtained in multiple independent crystal forms indicates that the mini-zipper is a stable structural element, whereas the C-terminal alpha-helix can adopt a broad range of orientations. Segmental alignment of the mini-zipper (mean pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of 0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 A C(alpha) rmsd displacement) is observed in the DCoH-bound peptide. Diabetes-associated mutations perturb distinct structural features of the HNF-1alpha domain. One mutation (L12H) destabilizes the domain but preserves structural specificity. Adjoining H12 side-chains in a native-like dimer are predicted to alter the functional surface of the mini-zipper involved in DCoH recognition. The other mutation (G20R), by contrast, leads to a dimeric molten globule, as indicated by its 1H-NMR features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn configuration enables specific interactions between the mini-zipper and the C-terminal coiled-coil.

Amino Acid Sequence↗
PubMed1985

Egg envelopes in vertebrates.

As the material presented in this chapter was being collated, our existing perceptions about the basic similarities of vertebrate (and indeed most, if not all, invertebrate) egg envelopes became increasingly strengthened. Perhaps without exception, all vertebrate and invertebrate eggs acquire a "vitelline" envelope. Interestingly, its filamentous ultrastructure and chemical composition--basically protein and carbohydrate--is similar in all species as is its permeability to large molecules. Furthermore, many (if not all) of its functions are shared among the animal phyla as is its potential to become altered at the time of fertilization and, in its altered state, to provide a new set of modi operandi. It provides sperm receptors that are generally species specific and helps prevent polyspermy; it protects the developing embryo yet yields at the time of hatching. In most vertebrate eggs (including some mammals), a jelly or albumen coat is added to the vitelline envelope. These components may vary immensely in thickness, but again their basic chemical composition is common to all. The functions of these envelopes, while perhaps somewhat less clear than those of the vitelline envelope, are related to species-specific fertilization and to embryonic protection. Albumen serves a nutritional role--most clearly shown in the birds. Finally, the shell membrane and shell present in diverse groups contribute additional adaptations for embryo protection. Vertebrate egg envelopes, then, are basically similar; the modifications, including the addition of shell membranes and shells in some groups, reflect adaptations to differing reproductive strategies and to the environmental exigencies with which the egg must cope. With the growth of our understanding about the structure, chemistry, function, and evolution of egg envelopes new questions will continually be formulated. Many will be the same as those asked years ago but they will be answered with newer techniques and with greater insight.

Animals↗
PubMed1980

Prevalence of diabetes among children of insulin-dependent diabetic mothers.

Eight diabetics were found among 464 children, mean age 11.2 years, of 311 unselected insulin-treated mothers. By a method of age correction the total diabetes prevalence among the children at the age of 25 years was calculated as 3.4%. Three children were non-insulin dependent and these patients and their mothers may belong to the autosomal dominant type of diabetes, so-called MODY. In two of the other five families the fathers also had insulin-dependent diabetes; in two more cases first or second degree paternal relatives were insulin-dependent diabetics. Thus the prevalence of insulin-dependent diabetes among the children of insulin dependent mothers married to non-diabetics is calculated as 1.5% at the age of 25 years.

Adolescent↗
PubMed1993

Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family.

Mutations were screened for in the glucokinase gene of 25 Japanese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segments under non-denaturing conditions and variants were sequenced. A variant pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCT-->ACT) of one of two alleles resulting in the mutation of Ala188-->Thr, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subjects. The proband had been diagnosed with Type 2 diabetes at the age of 62 years. Four other members of her family have the same mutation and all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 years, suggesting that her pedigree was maturity-onset diabetes of the young (MODY). All subjects with the Thr188 mutation show a decreased insulin secretory response during oral glucose tolerance testing. Mutations in the glucokinase gene associated with Type 2 diabetes have been previously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are required to determine the frequency of mutations in glucokinase among Japanese patients with Type 2 diabetes.

Adolescent↗
PubMed1995

Characterization of Japanese families with early-onset type 2 (non-insulin dependent) diabetes mellitus and screening for mutations in the glucokinase and mitochondrial tRNA(Leu(UUR)) genes.

Genetic linkage studies of families with early-onset type 2 diabetes have facilitated the identification of diabetes-susceptibility genes. In order to assess the feasibility of using linkage approaches to identify genes responsible for the development of type 2 diabetes in Japanese subjects, we examined our clinical records for multigenerational families suitable for genetic studies. We identified 16 families in which at least one subject was diagnosed with type 2 diabetes before 25 years of age. Seven of these families had a pattern of inheritance consistent with a diagnosis of maturity-onset diabetes of the young (MODY) and nine families showed a complex pattern of inheritance of type 2 diabetes with transmission of diabetes-susceptibility genes from both parents. The glucokinase and mitochondrial tRNA(Leu(UUR)) genes were screened for mutations in at least one affected subject from each family in order to assess the contribution of mutations in these genes to the development of the diabetes. No mutations were found, which suggests that the diabetes in these families resulted from mutations in other genes.

Adolescent↗
PubMedDate not supplied

Severe microvascular disease in type II diabetes of early onset. A family study.

Both early onset and late onset type II diabetes were present in one family of nine siblings. The three early onset type II diabetic siblings showed severe microvascular complications: proliferative retinopathy, diabetic nephropathy, and peripheral neuropathy. Early onset type II diabetes was not associated with any particular HLA haplotype. Early onset type II diabetes could be considered a clinical and genetic disease entity different from MODY type diabetes.

Adult↗
PubMed2001

Medical care from childhood to adulthood in type 1 and type 2 diabetes.

Diabetes mellitus comprises a heterogeneous group of diseases that have in common the development of macro- and microvascular complications. It is now possible to identify subjects at high risk of Type 1 or Type 2 diabetes, especially in the patient's family members. Preventive interventions are quickly becoming available, and can help delay the onset of the disease and thereby reduce complications in these subjects. Furthermore the correct etiological diagnosis of diabetes is fundamental in providing the best treatment for the patient. Maturity-onset diabetes of the young (MODY) syndrome should be suspected in cases of a subtle onset of diabetes and autosomal dominant inheritance. Mitochondrial DNA mutations should be considered when a diabetic patient also suffers from deafness or if there is a family history of this combination in the mother side of the family. Atypical diabetes has to be identified by the physician to avoid mistakes when the patient enters the non-insulin-dependent phase. In the case of Wolfram's syndrome a gene analysis for each family member should be performed to identify heterozygote subjects. Recently, many discoveries in genetics help us better understand the pathogenesis of the diseases and diagnose the monogenic form of diabetes more easily. If all family members are followed in the same center, clues from the family history are readily available for differential diagnosis and preventive interventions can be established more effectively.

Adolescent↗
PubMed2005

[Genetics of type 2 diabetes].

In the last years type 2 diabetes has reached almost epidemic proportions. More than 170 million individuals are affected worldwide, about 6 million in Germany. Manifestation of type 2 diabetes is determined by both environmental factors such as lack of physical exercise and overeating and a genetic predisposition. Despite enormous efforts in medical research to identify susceptibility loci and high risk alleles, the genetics of common type 2 diabetes (non-MODY) remain unknown. To date, only a few susceptibility genes have been identified (such as PPARG, KCNJ11, CAPN10). However, replication of initial studies is often difficult. This can be explained by both locus and allelic heterogeneity as well as ethnic differences between different populations. Studies in genetically isolated populations such as the Pima Indians are advantageous to identify susceptibility alleles. Despite some recent advances, it is not possible to predict an individual's risk of type 2 diabetes based on the presence of a certain disease-risk allele.

Biomarkers↗
PubMed2005

Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly.

Sudden and unexpected infant deaths can be unexplained [sudden infant death syndrome (SIDS)] or explained (non-SIDS) but risk factors including lower birthweight are similar in both groups. Mutations in the glucokinase (GK) gene result in Maturity Onset Diabetes of the Young type 2 (MODY 2) and are associated with lower birthweight. Low hepatic glucose-6-phosphatase (G6PC1) expression occurs in both low birthweight and SIDS infants. We investigated whether polymorphisms are prevalent in the GK and G6PC1 genes in infants who died suddenly and unexpectedly. Mutation analysis was performed by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) in samples from 126 infants who died suddenly and unexpectedly (78 SIDS, 48 non-SIDS) and from 70 healthy, living infants. G6PC1 promoter polymorphism significance was investigated by transfection of reporter gene constructs into a H4IIE cell line. Heterozygous GK polymorphisms were identified in 17.9% of SIDS and 20.8% of non-SIDS infants: two rare silent polymorphisms, Y215Y and S263S, in the coding region; a third rare polymorphism, -45G>A, in the hepatic promoter and the most prevalent polymorphism, c.484-29G>C, in a non-coding region upstream from the intron 4-exon 5 junction. A novel heterozygous polymorphism -77G>A in the G6PC1 promoter in 6.3% of non-SIDS and 2.9% of control infants decreased basal G6PC1 promoter activity (p<0.001). We describe three novel polymorphisms in the GK gene, S263S, -45G>A, and a common (14.3%) intronic substitution, c.484-29G>C, in infants who died suddenly and unexpectedly. We identified the first G6PC1 promoter polymorphism, which lowers expression, potentially increasing risk of hypoglycaemia and hence risk of sudden and unexpected death.

Animals↗
PubMed2002

Expression profile of MODY3/HNF-1alpha protein in the developing mouse pancreas.

AIMS/HYPOTHESIS: One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1alpha. The pattern of HNF-1alpha expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1alpha protein expression in the developing mouse pancreas. METHODS: Double immunofluorescence staining was carried out for HNF-1alpha and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1 alpha mutant mice. RESULTS: HNF-1alpha was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1alpha was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1alpha was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1alpha on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1alpha. However, HNF-1alpha immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1alpha. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1 alpha (-/-) mice, but expression was markedly decreased in the diabetic stage. CONCLUSION/INTERPRETATION: HNF-1alpha is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1alpha might play a role during development.

Aging↗
PubMed2002

Abnormal splicing of hepatocyte nuclear factor 1 alpha in maturity-onset diabetes of the young.

AIMS/HYPOTHESIS: Mutations in the HNF-1 alpha gene result in maturity-onset diabetes of the young (MODY); an early-onset, dominantly inherited form of diabetes caused by pancreatic beta-cell dysfunction. Splice site mutations represent approximately 10% of reported HNF-1 alpha mutations. No studies to date have investigated the effect of splice site mutations on mRNA processing because the tissues with abundant HNF-1alpha expression (liver, pancreas, kidney and gut) are not easily accessible for analysis. This study aimed to define the pathogenic mechanism in three novel splice site mutations by analysing illegitimate transcripts. METHODS: To assess the consequence of potential HNF-1 alpha splice site mutations we developed a nested reverse transcriptase PCR (RT-PCR) assay for the amplification of illegitimate HNF-1 alpha transcripts in Epstein Barr virus transformed lymphoblastoid cell lines. RESULTS: Sequencing the illegitimate HNF-1 alpha transcripts showed that the splice donor site mutation IVS8nt+1G>A leads to complete skipping of exon 8, the splice acceptor site mutation IVS4nt-2A>G causes skipping of exon 5 with the recruitment of a cryptic splice acceptor site within intron 5 and the cryptic splice acceptor site mutation (IVS7nt-6G>A) resulted in the skipping of exon 7. All three changes are predicted to result in premature termination of the HNF-1alpha protein, providing further evidence for their role as pathogenic mutations. CONCLUSION/INTERPRETATION: We conclude that the sequencing of illegitimate transcripts from lymphoblastoid cell lines is helpful in the assessment of intronic variation in HNF-1 alpha that could alter splicing. This analysis of the mRNA is required to define mutational mechanisms and confirm pathogenic status.

Adult↗
PubMed2003

T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.

AIMS/HYPOTHESIS: Mutations in hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known. METHODS: We screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in the HNF-4alpha gene. The transactivation ability of T130I-HNF-4alpha was assessed using reporter gene assay. RESULTS: The frequency of the T130I mutation was higher in Type 2 diabetic patients ( p=0.015, odds ratio 4.3, 95%CI 1.24-14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation ( p=0.006). Reporter gene analysis showed that T130I-HNF-4alpha transcriptional activity was not impaired compared with wild-type HNF-4alpha in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27-78% of wild type, p<0.05). CONCLUSION/INTERPRETATION: Our findings suggest that T130I-HNF-4alpha is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in the HNF-4alpha gene might be involved in the development of Type 2 diabetes in the Japanese population.

Age of Onset↗
PubMed2003

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1alpha gene in a Korean family with MODY3.

AIMS/HYPOTHESIS: After screening 16 Korean families with early onset Type 2 diabetes in search for hepatocyte nuclear factor (HNF) -1alpha gene mutation, we identified a novel missense mutation (R263L) associated with MODY phenotype. We studied the biological characteristics of the mutation and the potential functional consequences based on the crystallographic structure of HNF-1alpha in complex with DNA. METHODS: DNA from subjects with a familial form of early onset diabetes was isolated and HNF-1alpha was sequenced. The R263L substitution was generated by PCR-based sited-directed mutagenesis. Functional and biochemical studies were conducted by reporter assay using glucose-transporter type 2 (GLUT2) or insulin promoters and electrophoretic mobility shift assay, respectively. RESULTS: Transfection of wild-type HNF-1alpha increased the reporter activities of GLUT2 and insulin promoters in NIH3T3 and SK-Hep1 cells, while R263L mutant was defective in transactivation of those promoters. Both wild-type HNF-1alpha and R263L mutant could not transactivate GLUT2 and insulin promoters in MIN6N8 insulinoma cells. R263L mutant had a defective cooperation with its heterodimeric partner HNF-1beta or coactivator p300. R263L mutant protein displayed greatly reduced DNA binding ability, despite its comparable protein stability to the wild-type HNF-1alpha. CONCLUSION/INTERPRETATION: These results suggest that the mutation of HNF-1alpha at codon 263 from arginine to leucine leads to the development of MODY3 through decreased insulin production and defective glucose sensing. These findings are in good agreement with the crystal structure in which R263 makes hydrogen bonds with phosphorus atoms of DNA backbone to mediate the stable binding of HNF-1alpha homeodomain to the promoter.

Amino Acid Substitution↗
PubMed2003

Diabetes in the young: a paediatric and epidemiological perspective.

The spectrum of diabetes in the young has widened; it now includes monogenic diseases, for example the various forms of permanent and transient neonatal diabetes and MODY as well as the emerging obesity-associated Type 2 diabetes in late childhood, but the main form is still Type 1 diabetes. Age-related major medical, physiological, social and emotional problems make the clinical management of diabetes in children and adolescents a difficult task for the physician and the family. Overall glycaemic control remains moderate or poor despite a treatment schedule, which interferes with several elements of "normal" childhood. There is an up to tenfold geographical variation in the incidence of childhood Type 1 diabetes within Europe with relatively stable incidence rates in some countries (mainly northern), but dynamic increases in incidence in other countries (mainly central European).A number of nongenetic (environmental) factors have been associated with the risk of Type 1 diabetes. Among these, perinatal factors, early nutrition, growth and vaccinations, atopic diseases and vitamin D are discussed in detail. The important interplay between genes, organism and environment is illustrated with new genetic data supporting the importance of environmental pressures in the evolution of this major disease.Although Type 1 diabetes usually accounts for only a minority of the total impact of diabetes in a population, it is the predominant form of the disease in younger age-groups in most developed countries. It is estimated that on an annual basis almost 100 000 children younger than 15 years of age develop Type 1 diabetes worldwide. The autoimmune destruction of the pancreatic beta cells in Type 1 diabetes leads to absolute insulin dependence and a high rate of complications typically occurring at a relatively young age. Therefore, Type 1 diabetes places a particularly heavy burden on the individual, the family and health services.

Child↗
PubMed2003

For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure.

We review the progress in testing the thrifty phenotype hypothesis. Many human epidemiological studies both by ourselves and others have confirmed and extended the original observations on which the hypothesis was based. We are not aware of any contradictory findings and we emphasise the strength of the association between birth weight and the subsequent development of the metabolic syndrome. We have worked extensively experimentally to test the hypothesis in a rat model in which pregnant and/or lactating dams are fed a diet moderately restricted in proteins. The range of programming effects that we have discovered in this example of fetal and early postnatal growth restriction is listed and includes changes in hormone receptors, signalling molecules and regulatory enzymes. We have shown the model to develop diabetes, the metabolic syndrome and signs of premature renal failure. We summarise these and other similarities between the phenotype of this model and human Type 2 diabetes and the metabolic syndrome. The number of insults during early development which can lead to a similar outcome is discussed and the suggestion is made that the early life response to stress is limited in its flexibility with outcomes including ageing and decreased longevity. Our preliminary results indicate that some MODY genes could suggest pathways whereby the changes occur and that epigenetic changes during development are involved. We conclude that the way is now clear to discover early human markers of programming by early life growth restriction and to use these to devise strategies for the prevention of Type 2 diabetes.

Animals↗
PubMed2004

Transcriptional networks controlling pancreatic development and beta cell function.

Transcription factors provide the genetic instructions that drive pancreatic development and enable mature beta cells to function properly. To understand fully how this is accomplished, it is necessary to unravel the regulatory networks formed by transcription factors acting on their genomic targets. This article discusses recent advances in our understanding of how transcriptional networks control early pancreas organogenesis, embryonic endocrine cell formation and the differentiated function of adult beta cells. We discuss how mutations in several transcription factor genes involved in such networks cause Maturity onset diabetes of the young (MODY). Finally, we propose that pancreatic gene programs might be manipulated to generate beta cells or to enhance the function of existing beta cells, thereby providing a possible treatment of different forms of diabetes.

Animals↗