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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 &amp Metabolism (Impact Factor: 6.31). 07/2002; 87(6):2532-9. DOI: 10.1210/jc.87.6.2532
Source: PubMed

ABSTRACT 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.
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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.
    Human Mutation 11/2009; 30(11):1512-26. DOI:10.1002/humu.21110 · 5.05 Impact Factor
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    • "5 out of 9 GCK mutations as well as 3 out of 5 HNF1A mutations identified were new (Table 2). Among the GCK mutations we found 3 nonsense mutations, R186X (Katagiri H et al., 1992), E399X, and Y297X, 3 missense mutations including V203A (Froguel P et al., 1993), T206M (Massa O et al., 2001), and S383L (Barrio R et al., 2002), 2 novel deletions (K459fs610 and L144P) and one novel splice donor mutation (IVS5-1G>A) (Table 2). The HNF1A mutations included 2 missense mutations, namely R200Q (Hattersley AT., 1998) and A25P as well as 2 insertions, namely P291fsinsC (Yamagata K et al., 1996) and L383fsinsA, and the novel deletion R442fsX456 (Table 1). "
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    ABSTRACT: Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.
    Human Mutation 06/2005; 25(5):503-4. DOI:10.1002/humu.9334 · 5.05 Impact Factor
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