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

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.

Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients

“…In contrast to HNF-1a and GCK mutations, HNF-4a gene mutations are relatively uncommon worldwide [5,8,14,[17][18][19]. We found one single base substitution variant, T130I, in this study.…”

“…However, in France [9], the prevalence of MODY2 is 56% of MODY suspected families, higher than in MODY suspected families in Spain (25%) [12], Japan (1%) [13] and China (3%) [8]. Furthermore, prevalences in the same country have differed depending on the method of recruitment of the proband; in Spain, HNF-1a/MODY3 mutations were observed in 18% and 35% of families according to whether the proband was a child or an adult [12,14].…”

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

“…A previous study has showed that the frequencies of the same mutation were 2.0% (2/100) and 0% (0/100) in Japanese Type 2 diabetic and control subjects, respectively [13]. Combining the results of these two Japanese studies indicates that the T130I mutation is more strongly associated with [18,19,20,21,22,23,24,25,26]. The mean age at diagnosis was higher for patients with the T130I mutation (47.1±8.8 years, p=1.0×10 −6 ) than for those with other HNF-4α mutations.…”

International Union of Pharmacology. LXVI. Orphan Nuclear Receptors

“…Developmental: primary endoderm, liver, kidney, pancreas, stomach, intestine; adult: HNF␣-1 and -2-liver (hepatocytes), kidney, small intestine and colon but not in the pancreas; HNF␣-3 and -4-liver; HNF␣-7-pancreas, adult liver, small intestine, colon, stomach but not in the liver {Hs, Mm, Rn} ͓Northern blot, in situ hybridization, Western blot, immunohistology͔ 4,[35][36][37] Functional assays Measurement of receptor activity using CAT and luciferase reporter genes in HeLa, HepG2, Hep3B, Saos2, Caco-2, and HEK 293 cells {Hs} 4,28,38 ; ectopic overexpression of HNF-4␣ in fibroblasts induces a mesenchymal-to-epithelial transition, indicating that HNF-4␣ is a dominant regulator of the epithelial phenotype {Mm} 39 Mutant phenotype Targeted disruption of the HNF-4␣ gene results in embryonic lethality; the embryos initiate but do not complete gastrulation in the absence of HNF-4␣ {Mm} ͓knockout͔ 48,49 ; adult mice lacking hepatic HNF-4␣ expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations {Mm} ͓knockout͔ 39,50,51 ; mice lacking HNF-4␣ in pancreatic ␤ cells have hyperinsulinemia and, paradoxically, impaired glucose tolerance, as well as impaired glucose-stimulated insulin secretion and dysfunction of the K ATP channel activity {Mm} ͓conditional knockout͔ 52,53 Human disease Early-onset type 2 diabetes: due to the three SNPs (Asp 126 3Tyr, Asp 126 3His, Arg 154 3Gln) 54 ; late-onset type 2 diabetes: due to missense mutations in the LBD and F domain and 13 SNPs in the P2 promoter [55][56][57][58] ; MODY1: caused by mutations in several different human populations affecting either the DBD or LBD 32,[59][60][61][62][63] ; factor VII deficiency: caused by mutations in the HNF-4␣-binding site in the blood coagulation factor VII gene 64 ; hemophilia B Leyden: caused by mutations in the HNF-4␣-binding site in the blood coagulation factor IX gene [65][66][67] Biologically important isoforms TAk1 {Hs}; TR4a1 {Hs, Rn}: differ...…”