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1.
Maturity-onset diabetes of the young (MODY) is a subtype of early-onset diabetes mellitus which is characterized by autosomal dominant inheritance. Several genes are known to induce MODY : HNF4A/MODY1, GCK/MODY2, TCF1/MODY3, IPF1/MODY4, TCF2/MODY5 and NEUROD1/MODY6. We studied a Swiss family with 13 diabetic patients over 3 generations. The average age at diagnosis was 35 +/- 15 years (7 subjects before 30). In addition, 2 individuals had an abnormal oral glucose tolerance. The mutation present in this family was located in the DNA binding domain of HNF4A, a strongly conserved region across almost all species, and segregated in all the MODY patients. Identification of this missense mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals. 相似文献
2.
《Seminars in diagnostic pathology》2017,34(2):112-125
Hepatocellular adenomas are benign tumors with two major complications, bleeding and malignant transformation. The overall narrative of hepatocellular adenoma has evolved over time. Solitary or multiple hepatocellular developing in the normal liver of women of child bearing age exposed to oral contraceptives still represents the most frequent clinical context, however, new associations are being recognized. Hepatocellular adenoma is discovered on a background of liver diseases such as non-alcoholic steatohepatitis, vascular diseases, and alcoholic cirrhosis. Hepatocellular adenoma is also reported in men, young or older adults, and even in infants. On the morpho-molecular side, the great leap forward was the discovery that hepatocellular adenoma was not a single entity and that at least 3 different subtypes exist, with specific underlying gene mutations. These mutations affect the HNF1A gene, several genes leading to JAK/STAT3 pathway activation and the CTNNB1 gene. All of them are associated with more or less specific histopathological characteristics and can be recognized using immunohistochemistry either with specific antibodies or with surrogate markers. Liver pathologists and radiologists are the key actors in the identification of the different subtypes of hepatocellular adenoma by the recognition of their specific morphological features. The major impact of the classification of hepatocellular adenoma is to identify subjects who are at higher risk of malignant transformation. With the development of new molecular technologies, there is hope for a better understanding of the natural history of the different subtypes, and, particularly for their mechanisms of malignant transformation. 相似文献
3.
The genetic abnormality in the beta cell determines the response to an oral glucose load 总被引:6,自引:3,他引:6
Stride A Vaxillaire M Tuomi T Barbetti F Njølstad PR Hansen T Costa A Conget I Pedersen O Søvik O Lorini R Groop L Froguel P Hattersley AT 《Diabetologia》2002,45(3):427-435
Aims/hypothesis: We assessed how the role of genes genetic causation in causing maturity-onset diabetes of the young (MODY) alters the response
to an oral glucose tolerance test (OGTT).
Methods: We studied OGTT in 362 MODY subjects, from seven European centres; 245 had glucokinase gene mutations and 117 had Hepatocyte
Nuclear Factor –1 alpha (HNF-1α) gene mutations.
Results: BMI and age were similar in the genetically defined groups. Fasting plasma glucose (FPG) was less than 5.5 mmol/l in 2 %
glucokinase subjects and 46 % HNF-1
α subjects (p < 0.0001). Glucokinase subjects had a higher FPG than HNF-1
α subjects ([means ± SD] 6.8 ± 0.8 vs 6.0 ± 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 ± 2.3 vs 11.2 ± 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h – fasting) (2.1 ± 2.3 vs 5.2 ± 3.9 mmol/l, p < 0.0001). The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1
α) or 2-h values (19 % vs 44 %) were used. Fasting and 2-h glucose values were not correlated in the glucokinase subjects (r = –0.047, p = 0.65) but were strongly correlated in HNF-1
α subjects (r = 0.8, p < 0.001). Insulin concentrations were higher in the glucokinase subjects throughout the OGTT.
Conclusion/interpretation: The genetic cause of the beta-cell defect results in clear differences in both the fasting glucose and the response to an
oral glucose load and this can help diagnostic genetic testing in MODY. OGTT results reflect not only the degree of hyperglycaemia
but also the underlying cause. [Diabetologia (2002) 45: 427–435]
Received: 13 September 2001 and in revised form: 26 November 2001 相似文献
4.
E Bellacchio R Stallone T Palladino S Mastroianno L Zelante M Sacco V Trischitta M Carella 《Clinical genetics》2013,83(1):83-87
Delvecchio M, Ludovico O, Bellacchio E, Stallone R, Palladino T, Mastroianno S, Zelante L, Sacco M, Trischitta V, Carella M. MODY type 2 P59S GCK mutant: founder effect in South of Italy. Mutations in the glucokinase (GCK) gene are the most frequent cause of maturity onset diabetes of the young (MODY) in Italy. We evaluated GCK mutations in 32 unrelated patients younger than 18 years who had been diagnosed with MODY. Eleven different GCK heterozygous mutations were identified in 22 (68.7%) of the 32 probands. Nine mutations were missense and two were nonsense. Three of these mutations (E17X, P59S and E372X) have not been described previously and were shown to be associated with hyperglycaemia. Several prediction methods suggested that the E17X and E372X mutations result in a premature truncated protein and that the P59S mutation is pathogenic. This idea was further supported by evidence suggesting that Proline 59 is a highly conserved amino acid residue and that the P59S mutation does not appear to be present in non‐diabetic controls and in sequence variant databases. Furthermore, this mutation was found in six (27.3%) of the patients from the same geographical area, Gargano, pointing to the existence of a founder effect, which was confirmed by microsatellite analysis. 相似文献
5.
Konstantina Patouni Ondrej Cinek Stepanka Pruhova Lenka Elblova Maria Xatzipsalti Amalia Sertedaki Andriani Vazeou 《European journal of medical genetics》2021,64(9):104264
BackgroundMaturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now.Case reportA female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant.ConclusionDigenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed. 相似文献
6.
Kevin Colclough Christine Bellanne‐Chantelot Cecile Saint‐Martin Sarah E. Flanagan Sian Ellard 《Human mutation》2013,34(5):669-685
Maturity‐onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young‐onset (typically <25 years), noninsulin‐dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor‐1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor‐4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ~50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost‐effective gene analysis for all patients with young onset diabetes. 相似文献
7.
A 12q24.31 interstitial deletion in an adult male with MODY3: Neuropsychiatric and neuropsychological characteristics 下载免费PDF全文
8.
《Diabetes & metabolism》2020,46(5):400-402
AimThe aim of the present study was to identify the affected gene in a French family with maturity-onset diabetes of the young (MODY) using whole-exome sequencing (WES).MethodsWES was performed in one patient with MODY, and candidate variants were confirmed in members of the immediate family by Sanger sequencing.ResultsIn the proband, a new heterozygous missense mutation (c.340A>C) was identified in the NEUROD1 gene by WES analysis and confirmed by Sanger sequencing. Additional Sanger sequencing of the proband's sister and mother revealed the same heterozygous mutation. The proband and his sister displayed typical clinical characteristics of MODY, while their mother had the same typical MODY features except for later onset. When clinical and biological profiles were established for all three patients, the severity of diabetes-related complications varied substantially from one family member to another.ConclusionA novel missense mutation found in NEUROD1 was associated with MODY 6 features in a single French family. 相似文献
9.
Nakamura A Ishidu K Tajima T 《Journal of clinical research in pediatric endocrinology》2012,4(2):104-106
Maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the HNF1A gene. Liver adenomatosis has been reported in MODY3 patients. The patient reported in this paper is a Japanese girl who first developed hepatomegaly, fatty liver, and hepatic dysfunction at age 5 years. Liver biopsy demonstrated steatosis and degeneration of hepatocytes. At that time, blood glucose and HbA1c levels were within normal ranges. Elevated HbA1c was noticed 4 years later, but islet cell and glutamic acid decarboxylase antibodies were not detected in the serum. Therefore, MODY3 was suspected and subsequent analysis of the HNF1A gene identified a heterozygous germline splice donor-site mutation in intron 9. MODY3 patients should be screened by non-invasive liver imaging, and careful follow-up of liver disease should be performed. 相似文献
10.
Petra Dusatkova Mingyan Fang Stepanka Pruhova Anette P. Gjesing Ondrej Cinek Torben Hansen Oluf B. Pedersen Xun Xu Jan Lebl 《Diabetes research and clinical practice》2014
We report the first results from whole-exome sequencing performed in families with Maturity-Onset Diabetes of the Young without a known genetic cause of diabetes (MODYX). This next generation sequencing technique pointed out that routine testing of MODY needs constant awareness and regular re-evaluation of both clinical criteria and primer sequences. 相似文献