Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1α and glucokinase

Abstract

Maturity-onset diabetes of the young (MODY), a monogenic subset of Type II (non-insulin-dependent) diabetes mellitus, is caused by mutations in at least five different genes: HNF-4a-MODY1 [1], GCK-MODY2 [2], HNF-1a-MODY3 [3], IPF-1-MODY4 [4], and HNF-1b-MODY5 [5]. MODYis an autosomal dominant disorder with an onset typically under 25 years of age, and usually accounts for 2 % to 5 % of all patients with Type II diabetes but a true estimate is challenging because patients with MODY are often wrongly diagnosed as having Type I or Type II diabetes. Late-onset Type II diabetes is a polygenic heterogeneous disorder whose pathogenesis is not clear. We regard Type II diabetes as a genetically continuous spectrum of early-onset to late-onset diabetes, partially due to mutations in the MODY genes. The prevalence of HNF-1a, GCK and HNF-4a mutations in MODY patients varies among different populations. Up to now four missense mutations in the MODY2 [6,7] and none in the MODY3 gene have been identified in Italian MODY patients. The aim of our study Diabetologia (2001) AbstractAims/hypothesis. Maturity-onset-diabetes of the young (MODY) is caused by mutations in at least five different genes. Our aim was to determine the prevalence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus. Methods. We screened 28 Italian early-onset Type II diabetic families (diagnosis < 35 years) for mutations in the hepatic nuclear factor-4a, (MODY1), glucokinase (MODY2) and hepatic nuclear factor-1a (MODY3). Both strands of exons, flanking introns and minimal promoter regions of the above-mentioned genes were amplified using polymerase chain reaction and were sequenced directly. Results. We identified four different mutations, three of which are not described, (W113X, G42P43fsCC ® A, H514R) and four new polymorphisms (G184G, T513T, IVS3-nt47delG, IVS1-nt53C ® G) in the hepatic nuclear factor-1a gene, two new potential mutations (G44S, IVS4nt + 7C ® T) and three new polymorphisms (promoter-nt84C ® G, IVS9 + nt8C ® T, IVS9 + nt49G ® A) in the glucokinase gene, and a new polymorphism (IVS1c-nt11T ® G) in the hepatic nuclear factor-4a gene. Conclusion/interpretation. Mutations in the hepatic nuclear factor-1a and glucokinase are associated with Type II diabetes in 14 % and 7 % of Italian families, respectively. Our findings provide an impetus for screening Italian MODY and early-non Type II diabetic families for mutations in the above mentioned genes to identify relatives at risk who could benefit from primary prevention care. [Diabetologia (2001) 44: 1326±1329]Keywords Type II diabetes mellitus, genetics, hepatocyte nuclear factor-1a, hepatocyte nuclear factor-4a, glucokinase, MODY, Italian, mutation, polymorphism. Corresponding author: C. Gragnoli, Molecular Endocrinology, WEL 320, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA E-mail: cgragnoli@partners.org Abbreviations: HNF, hepatocyte nuclear factor; GCK, glucokinase; IPF-1, insulin promoter factor-1...

Low Prevalence of HNF1A Mutations After Molecular Screening of Multiple MODY Genes in 58 Italian Families Recruited in the Pediatric or Adult Diabetes Clinic From a Single Italian Hospital

“…HNF1A mutations ranked second (14%) in the pediatric clinic but accounted for a similar proportion (20%) among adults. This result was in keeping with previous data (14%) obtained in a total of 42 Italian families with autosomal dominant diabetes recruited in Central (Tuscany, Sardinia) and Northern (Piedmont) Italy (4,5), and it was in sharp contrast with results obtained in Northern Europe (3). The major strength of our investigation is that the two groups of patients were recruited from the same geographic area and screened in the same laboratory.…”

“…cians contributed to the recruitment and to the clinical and the genetic counseling for the referred patients included in this study. Antonella Marucci, 3 Valeria Grasso, 5 Vincenzo Trischitta, 3,6 Massimo Carella, 4 and Fabrizio Barbetti 5,7 e258…”

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

“…The diagnosis of MODY is very important in children and adolescent diabetic patients [3,4]. Although the true relative prevalence of six distinct MODY subtypes is unknown and varies substantially in studies in various populations [5][6][7][8][9][10], mutations in the genes encoding HNF1α and GCK are the most prevalent. Mutations in GCK (MODY2) account for 7% -41% [8,9], whereas mutations in TCF1 (MODY3) may account for 11% -63% of mutations in subjects with clinically diagnosed MODY.…”

“…Although the true relative prevalence of six distinct MODY subtypes is unknown and varies substantially in studies in various populations [5][6][7][8][9][10], mutations in the genes encoding HNF1α and GCK are the most prevalent. Mutations in GCK (MODY2) account for 7% -41% [8,9], whereas mutations in TCF1 (MODY3) may account for 11% -63% of mutations in subjects with clinically diagnosed MODY. Mutations in HNF4α (MODY1) are less frequent and may account for 2% -5% of subjects with MODY [7,10].…”

“…Mutations in IPF1 and NEUROD1 are rare and have been identified in single families. Interestingly, unknown MODY genes, known as MODYX, may be responsible for up to 79% of cases of MODY depending on sampling and the stringency of inclusion criteria [8]. This finding suggests that additional MODY genes are likely to exist.…”