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PubMed2005

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients.

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.

Adult↗
PubMed2005

Monochorionic diamniotic infants without twin-to-twin transfusion syndrome.

BACKGROUND: Monochorionic-diamniotic twins (MoDi) occur in 0.3% of all pregnancies. Twin-to-twin transfusion syndrome (TTS) that occurs in 20% of MoDi pregnancies is associated with high perinatal morbidity and mortality. MoDi twins without TTS are more frequent (80%) but have been scarcely reported. OBJECTIVE: To study perinatal morbidity and mortality of 74 MoDi twin sets without TTS and to compare it to that of 38 sets of MoDi twins with TTS. METHODS: Chorionicity was determined by gender and placental examination. Gestational age (GA) was set by sonography and pediatric examination. TTS was diagnosed clinically and by sonography, discordance was defined by twins birth weight difference > or =20%, and fetal growth restriction was determined by using a twin-specific nomogram. RESULTS: MoDi twin pregnancies without and with TTS were similar in demographics, live births, history of preeclampsia, fetal distress and cesarean delivery. They were different (p<0.01) in discordant pregnancies (36 and 79%), GA at delivery (32 and 29 weeks) intrauterine growth restriction (39 and 89%) and neonatal mortality (12 and 36%). Concordant (47 sets) and discordant (27 sets) MoDi twins without TTS were clinically similar. CONCLUSIONS: MoDi twins without TTS have high rates of birth weight discordance, fetal growth restriction, fetal distress, prematurity and cesarean delivery. Although their perinatal mortality is low, the reported occurrence and the short- and long-term impacts of fetal and neonatal morbidities warrants attention.

Amnion↗
PubMed2000

Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families.

OBJECTIVE: To investigate the frequencies of the major maturity-onset diabetes of the young (MODY) subtypes in a panel of Spanish families and to assess phenotypic differences in patients with the different subtypes of MODY. METHODS: Forty-eight subjects from twenty families with clinical diagnosis of MODY were studied. They underwent a standardised clinical examination and a 75-g oral glucose tolerance test (OGTT) was performed. Estimations of insulin sensitivity (%S) and insulin secretion capacity (%B) were calculated by the computer-solved homeostasis model assessment (HOMA). Mutations in the coding regions of hepatocyte nuclear factor (HNF)-4alpha/MODY1, glucokinase (GCK/MODY2) and HNF-1alpha/MODY3 genes were investigated by single strand comformation polymorphism and sequencing analysis. RESULTS: Mutations in the GCK and HNF-1alpha genes were observed in 5 (25%) and 7 (35%) families respectively. Novel mutations included R385X, M238fsdelT, V226fsdelTinsAA and S418-7del11 in the GCK gene, and S121fsdelC, V133M, R159Q and V259D in the HNF-1alpha gene. No MODY1 families were found. Subjects which were neither MODY2 nor MODY3 (MODY-X) had a higher fasting glucose than subjects in the other groups. Insulin secretion capacity was similar in the three groups and the insulin sensitivity was decreased in MODY-X subjects. Glucose levels were significantly higher and insulin levels significantly lower, throughout the OGTT, in MODY3 compared with MODY2 subjects. CONCLUSIONS: Mutations in the GCK/MODY2 and HNF-1alpha/MODY3 genes account for the majority of cases in a panel of Spanish MODY families, with MODY3 being the most frequent subtype. The relative frequencies and the clinical characteristics of these MODY subtypes are in agreement with data previously reported in other European populations. MODY-X patients seem to present a heterogeneous clinical profile.

Adult↗
PubMed2000

Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance. RESULTS: A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance. CONCLUSIONS: Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.

Adolescent↗
PubMed2026

Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.

CONTEXT: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. OBJECTIVE: To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes. METHODS: Comprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability. RESULTS: Four variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to maternal hyperglycemia in utero, which may also have contributed to this early onset. CONCLUSION: Functional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.

Humans↗
PubMed2003

A novel mutation in exon 5 of the glucokinase gene in an Argentinian family with maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is caused by mutations in at least six different genes, including the glucokinase gene (MODY 2) and genes encoding the tissue-specific transcription factors (MODY 1 and MODY 3-6). To determine the presence of mutations in MODY 2 in four members of a family who have the clinical characteristics of MODY, we performed polymerase chain reaction and single strand conformation polymorphism screening, followed by DNA sequencing. We found a novel mutation which consisted of the deletion of a cytosine in the position 2 of the exon 5 codon 168. This mutation produced a frame shift which determines a stop codon at position 203 in exon 6. The identification of a mutation in glucokinase gene and transcription factor genes in patients with early-onset diabetes confirms the diagnosis of MODY and has important implications for clinical management.

Adult↗
PubMed2001

Single-strand conformation polymorphism analysis of the glucose transporter gene GLUT1 in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY), an autosomal dominant, early-onset form of type-2 diabetes, is caused by mutations in five different genes all leading to defect(s) in the pancreatic beta cell. However, some patients with this form of diabetes do not bear a mutation in any of the known (MODY1-MODY5) loci, a notion prompting the search for new MODY genes. Clinical and genetic data point toward a defect in beta cell function in the majority of patients with MODY, and partners of the glucose-sensing device are reasonable functional candidates. The high-capacity glucose transporter GLUT2 has the ideal kinetic features for performing this task. However, complete GLUT2 deficiency in humans leads to hepato-renal glycogenosis (Fanconi-Bickel syndrome), and heterozygous GLUT2 mutations apparently behave in a recessive manner. Furthermore, in the human beta cell GLUT1 mRNA is predominant when compared to GLUT2 and glucose influx appears to be largely mediated by this low-Km transporter. Thus, we looked for the presence of sequence variants by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) within the GLUT1 gene in 90 Italian pedigrees negative at the search for mutations in glucokinase (MODY2) and hepatocyte nuclear factor-1alpha (MODY3), the two genes responsible for about 60% of MODY cases in Italian children. We found three already described silent mutations and a new single base deletion in position -173 of the 5' regulatory region. The -173de1A variant, which was detected in the heterozygous or homozygous state in 30.8% of MODY patients examined and is located in a Nuclear Factor Y binding sequence, is not associated with hyperglycemia in affected relatives of MODY probands. In conclusion, it appears from these results that the glucose transporter gene GLUT1 is unlikely to play a major role in the etiology of MODY diabetes.

Adolescent↗
PubMed1999

No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France.

AIMS/HYPOTHESIS: The identification of mutations in hepatocyte nuclear factors-1alpha, -4alpha, -1beta and insulin promoter factor-1 in maturity onset diabetes of the young (MODY) has highlighted the role that transcription factors may have in the development of diabetes. This result has focused molecular genetic studies of diabetes on other transcription factors expressed in the pancreatic beta cell. The basic helix-loop-helix transcription factor BETA2/NEUROD1 (gene symbol, NEUROD1) and the paired box homeodomain transcription factor PAX4 (PAX4) have an important role in islet and beta-cell development. We have examined the contribution of these transcription factors to the development of MODY and late-onset Type II (non-insulin-dependent) diabetes mellitus. METHODS: Linkage studies have been done in MODY families reported to have no mutations in the five known MODY genes and in affected sibling pairs from families with late-onset Type II diabetes. Mutation screening of the coding regions of both genes was also realised by SSCP followed by sequencing in MODY patients and in probands with late-onset Type II diabetes. RESULTS: There was no evidence of linkage with the markers for NEUROD1 and PAX4 either with MODY or late-onset Type II diabetes. Mutation screening showed single nucleotide polymorphisms, several of which resulted in amino acid substitutions: NEUROD1, Ala45Thr; PAX4, Pro321His and Pro334Ala. These amino acid sequence variants were not associated with Type II diabetes. CONCLUSION/INTERPRETATION: Our results indicate that NEUROD1 and PAX4 are not a common cause of either MODY or late-onset Type II diabetes in the French Caucasian population.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state.

AIMS/HYPOTHESIS: To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4 alpha) and MODY3 (HNF-1 alpha) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus. METHODS: Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion. RESULTS: Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p < 0.05 and p < 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = -0.447, p < 0.001) and subjects from Type II diabetic families (r = -0.426, p < 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage. CONCLUSION/INTERPRETATION: Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity.

Adult↗
PubMed2000

Molecular and genetic bases for maturity onset diabetes of youth.

Maturity onset diabetes of youth (MODY) occurs in children, adolescents and young adults as a non-insulin-requiring form of diabetes mellitus that is inherited as an autosomal dominant trait. Maturity onset diabetes of youth in whites presents subtly similar to type 2 diabetes in adults. In contrast, a MODY variant that occurs in young blacks, termed atypical diabetes mellitus, presents as an acute-onset form of diabetes. Months to years after diagnosis, atypical diabetes mellitus reverts to a noninsulin requiring course similar to MODY in whites. Five molecular causes for MODY have been identified: mutations in four transcription factors and mutations in one enzyme (glucokinase). Transcription factors regulate gene expression within cells. Mutations in hepatocyte nuclear factor-4alpha, hepatocyte nuclear factor-1alpha, insulin promoter factor-1 and hepatocyte nuclear factor-1beta, respectively, cause MODY1, MODY3, MODY4, and MODY5. Glucokinase is the glucosensor of the beta cell. MODY2 is caused by glucokinase mutations. Although testing for MODY mutations is only available in research laboratories, a careful history and review of the patient's clinical course can often allow the clinician to diagnose MODY. The diagnosis of MODY has implications for the clinical management of the patient's diabetes.

Adolescent↗
PubMed2005

Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1.

AIMS/HYPOTHESIS: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by an autosomal dominant inheritance, an early clinical onset, and a primary defect in beta-cell function. The aims of the present study were to examine the prevalence and nature of mutations in the three common MODY genes, HNF4A, GCK, and TCF1, in Danish patients with a clinical diagnosis of MODY and to describe metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. METHODS: Seventy-eight unrelated subjects of Danish Caucasian origin (29 men, 49 women) and their 351 family members were examined. The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing. RESULTS: We identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Our findings suggest a relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. CONCLUSIONS: Forty-nine percent of the families carried mutations in the three examined MODY genes. Our findings highlight that unidentified MODY genes may play a central role for diabetes characterized by autosomal dominant transmission. Furthermore, baseline measurements of various anthropometric and biochemical variables are not appropriate markers of MODYX.

Adolescent↗
PubMed1997

Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters.

The aim of our study was to investigate the relative prevalence of the different forms of diabetes in young adults and their respective clinical characteristics. Included were 51 nonobese patients (BMI < 27 kg/m2) with diabetes diagnosed before age 40, excluding typical IDDM. Each patient was subjected to screening for glucokinase gene (MODY2) and mitochondrial DNA (at nucleotide 3243) mutations, to HLA class II genotyping, and screening for the presence of islet cell antibodies (ICAs) and anti-GAD antibodies. Informative families were analyzed for linkage of diabetes to chromosome 12q (MODY3). Based on clinical criteria, patients were subdivided into MODY (n = 19) and non-MODY (n = 32). In the MODY group, we identified three patients with MODY2, one with the 3243 mitochondrial mutation, and another with autoimmune diabetes. One of the five MODY families available for linkage study was shown to have MODY3. In the non-MODY group, we found five patients with autoimmune diabetes and one with MODY2. No clinical parameter was helpful to classify patients in one of these subclasses of diabetes; however, the glucagon-stimulated C-peptide was useful to discriminate between MODY2 patients and the others. In conclusion, young and lean non-insulin-dependent diabetic patients constitute a very heterogeneous group, although they present similar clinical characteristics. The clinical distinction of MODY and non-MODY patients allows correct classification in, at most, 75% of the patients and thus is not sufficient to predict clinical course. However, immunological and genetic parameters allowed us to classify only 25% of the patients in specific diagnostic classes.

Adult↗
PubMed2003

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.

Adolescent↗
PubMed2001

[Diabetes mellitus].

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.

Diabetes Mellitus↗
PubMed1998

Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) can be defined by the clinical characteristics of early-onset Type 2 (non-insulin-dependent) diabetes and autosomal dominant inheritance. Mutations in four genes have been shown to cause MODY: glucokinase, hepatic nuclear factor 1 alpha (HNF1alpha), hepatic nuclear factor 4 alpha (HNF4alpha) and insulin promoter [corrected] factor 1 (IPF1). In white Caucasians it is now possible to define the gene in most patients with a clinical diagnosis of MODY. Each gene involved in MODY has its own specific clinical and physiological characteristics. Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications. The principle pathophysiology is stable beta-cell dysfunction characterized by reduced sensing of glucose by the pancreas. Patients with mutations in HNF1alpha have normal glucose tolerance in early childhood and usually present with symptomatic diabetes in their late teens or early adulthood. They show increasing hyperglycaemia and treatment requirements with frequent microvascular complications. The underlying defect is progressive beta-cell failure, with the early lesion characterized by failure to increase insulin secretion with increasing glucose levels. Patients with HNF4alpha and IPF1 mutations show a similar clinical picture to HNF1alpha although diabetes may be diagnosed later. There are other patients with MODY in whom the genetic defect is still unknown. Molecular genetic testing in patients with diabetes offers the possibility of making a firm diagnosis of MODY and allows prediction of the future clinical course. The role of predictive testing in non-diabetic subjects within families is uncertain at present. Preliminary evidence suggests that maintaining insulin sensitivity by avoiding obesity and regular physical exercise may help delay the onset of diabetes.

Adolescent↗
PubMed1997

A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes.

Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous disorder of glucose homeostasis. Maturity-onset diabetes of the young (MODY) is a monogenic subtype of NIDDM characterised by early-onset (< 25 years) and autosomal dominant inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene have recently been shown to cause MODY. The incidence of mutations in this gene in MODY and late-onset NIDDM is not known. We have developed a rapid specific polymerase chain reaction test for HNF-1 alpha mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers to detect length polymorphisms resulting from frameshift mutations. With this method, we have screened 102 MODY probands, viz. 60 defined according to strict diagnostic criteria (autosomal dominant inheritance and at least one member diagnosed age < 25 years) and 95 late-onset NIDDM probands (diagnosed 35-70 years with > or = 1 affected relative), for the presence of 9 known HNF-1 alpha frameshift mutations, including 6 that occur at two sites for recurring mutation (residues 291/292 and 379). Mutations were detected in 11 of the strictly defined MODY probands and one mutation was also found in a single subject with early-onset NIDDM but no family history of the disease. The HNF-1 alpha frameshift mutations were not detected in any late-onset NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM. Our results indicate that the prevalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having a frequency of 13%.

Adult↗
PubMed1991

Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q.

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterized by an early age of onset, usually before 25 years of age, and an autosomal dominant mode of inheritance. The largest and best-studied MODY pedigree is the RW family. The majority of the diabetic subjects in this pedigree has a reduced and delayed insulin-secretory response to glucose, and it has been proposed that this abnormal response is the manifestation of the basic genetic defect that leads to diabetes. Using DNA from members of the RW family, we tested more than 75 DNA markers for linkage with MODY. A DNA polymorphism in the adenosine deaminase gene (ADA) on the long arm of chromosome 20 was found to cosegregate with MODY. The maximum logarithm of odds (lod score) for linkage between MODY and ADA was 5.25 at a recombination fraction of 0.00. These results indicate that the odds are greater than 178,000:1 that the gene responsible for MODY in this family is tightly linked to the ADA gene on chromosome 20q.

Adenosine Deaminase↗
PubMed1994

Genetic analysis of glucokinase and the chromosome 20 diabetes susceptibility locus in families with type 2 diabetes.

Mutations of the glucokinase gene (chromosome 7p) have been shown to cause some cases of familial maturity onset diabetes of youth (MODY) but few, if any, cases of late onset familial Type 2 diabetes. A further single large pedigree with MODY has shown linkage to a marker for the adenosine deaminase gene (ADA, chromosome 20q), although the diabetes susceptibility gene at this locus has not been identified. We have studied members of 19 families with familial Type 2 diabetes (including 10 European families, 6 families from the Indian subcontinent, and 3 families of Afro-Caribbean origin), 2 of which were of MODY type (and both European), with a glucokinase marker and a marker linked to ADA, to examine whether glucokinase, or the unknown defect on chromosome 20, are implicated in diabetes in our pedigrees. Several models were constructed for standard two-point linkage analysis. Glucokinase is not the cause of diabetes in all of these families but was excluded in only one MODY family. It was possible to exclude both loci in the second MODY pedigree. No evidence was found of linkage to either marker in this multi-ethnic population under the models used. At least one further locus is involved in determining susceptibility to MODY.

Adult↗