Nine Novel Mutations in Maturity-Onset Diabetes of the Young (MODY) Candidate Genes in 22 Spanish Families

Pediatric Diabetes Unit, Ramón y Cajal Hospital, University of Alcalá, Carretera Comenar Viejo Km. 9.4, 28034 Madrid, Spain.
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 07/2002; 87(6):2532-9. DOI: 10.1210/jc.87.6.2532
Source: PubMed


The aims of this study were to estimate the prevalence of major maturity-onset diabetes of the young (MODY) subtypes in Spanish MODY families and to analyze genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the glucokinase (GCK), hepatic nuclear factor- HNF-1alpha and HNF4alpha genes using PCR-single strand conformation polymorphism and/or direct sequencing. In families carrying GCK mutations, the influence of genetic defects on fetal growth was investigated by comparing the birth weights of 32 offspring discordant for the mutations. Mutations in MODY genes were identified in 64% of the families. GCK/MODY2 mutations were the most frequently found, in 41%: seven novel (R369P, S411F, M298K, C252Y, Y108C, A188E, and S383L) and 2 already described mutations. Four pedigrees (18%) harbored mutations in the HNF-1alpha/MODY3 gene, including a previously unreported change (R271G). One family (4%) carried a novel mutation in the HNF-4alpha gene (IVS5-2delA), representing the first report of a MODY1 pedigree in the Spanish population. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3. Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin. The MODY1 patient was diagnosed at 15 yr of age. She developed intermittent microalbuminuria despite good metabolic control, and severe late-onset complications were common within her family. Mutations in the GCK/MODY2 gene are the most common cause of MODY in our population as recruited from pediatric and adolescent index patients. The inheritance of GCK defects by the fetus results in a reduction of birth weight. Clinical expression of MODY3 and MODY1 mutations, the second and third groups of defects found, was more severe, including the frequent development of chronic complications.

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    • "Mutations in the genes encoding HNF1A and GCK are by far the most prevalent. Mutations in GCK (MODY 2) account for 7 to 41% (Gragnoli, 2001; Barrio et al., 2002), whereas mutations in TCF1 (MODY 3) may account for 11 to 63%, (Pruhova et al., 2003) of mutations in subjects with clinically diagnosed MODY. Mutations in HNF4A (MODY1) are less frequent and may account 2 to 5% of subjects with MODY (Pruhova et al., 2003). "
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    ABSTRACT: The pandemic of metabolic disorders is accelerating in the urbanized world posing huge burden to health and economy. The key pioneer to most of the metabolic disorders is insulin dependent diabetes mellitus or Type 1 diabetes mellitus (T1DM) and non-insulin dependent diabetes mellitus commonly known as Type 2 diabetes mellitus (T2DM). Both of these forms of diabetes are polygenic and multifactorial. A newly discovered form of diabetes is Maturity Onset Diabetes of the Young (MODY). MODY is monogenic form of diabetes inherited as autosomal dominant anarchy. This piece of writing presents a concise portrayal to MODY. In this article this new form of diabetes is introduced, its different subtypes and clinical characteristics are discussed.
    Full-text · Article · Feb 2011
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    • "But Mutations in HNF4α (MODY1) are less frequent and may account for 2-5% of subjects with MODY [8,25,26]. Only 26 families worldwide have been diagnosed with MODY1 [9,27], although, we found HNF4α mutation (Val/Met255) in 3 families of our study group. This substitution changes an amino acid sequence of the HNF4α protein. "
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    ABSTRACT: Hepatocyte nuclear factor 4alpha (HNF4alpha) is a nuclear receptor involved in glucose homeostasis and is required for normal beta cell function. Mutations in the HNF4alpha gene are associated with maturity onset diabetes of the young type 1 (MODY1). The aim of the present study was to determine the prevalence and nature of mutations in HNF4alpha gene in Iranian patients with a clinical diagnosis of MODY and their family members. Twelve families including 30 patients with clinically MODY diagnosis and 21 members of their family were examined using PCR-RFLP method and in case of mutation confirmed by sequencing techniques. Fifty age and sex matched subjects with normal fasting blood sugar (FBS) and Glucose tolerance test (GTT) were constituted the control group and investigated in the similar pattern. Single mutation of V255M in the HNF4alpha gene was detected. This known mutation was found in 8 of 30 patients and 3 of 21 individuals in relatives. Fifty healthy control subjects did not show any mutation. Here, it is indicated that the prevalence of HNF4alpha mutation among Iranian patients with clinical MODY is considerable. This mutation was present in 26.6% of our patients, but nothing was found in control group. In the family members, 3 subjects with the age of <or=25 years old carried this mutation. Therefore, holding this mutation in this range of age could be a predisposing factor for developing diabetes in future.
    Full-text · Article · Dec 2009 · Cardiovascular Diabetology
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    • "There is some discrepancy in the literature on the prevalence of GCK-MODY in European Caucasian MODY families. In the UK, the prevalence is reported as 10–20% [Thomson et al., 2003], in France as 46–56% [Froguel et al., 1993], 41–61% in Italy [Mantovani et al., 2003; Massa et al., 2001], 25–80% in Spain [Barrio et al., 2002; Costa et al., 2000; Estalella et al., 2007], 31% in the Czech Republic [Pruhova et al., 2003], 12% in Norway [Sagen et al., 2008], and 10% in Denmark [Johansen et al., 2005]. The considerable variation in prevalence can be attributed to the way in which patients were ascertained and recruited for the various studies [Massa et al., 2001]. "
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    ABSTRACT: Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta-cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper- and hypoglycemia has implications for the clinical course and clinical management of their disorder.
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