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ABSTRACT Objective We aimed to identify the frequency of monogenic diabetes, which is poorly studied in multiethnic populations, due to GCK or HNF1A mutations in patients with suggestive clinical characteristics from the Brazilian population, as well as investigate if the MODY probability calculator (MPC) could help patients with their selection. Subjects and methods Inclusion criteria were patients with DM diagnosed before 35 years; body mass index < 30 kg/m2; negative autoantibodies; and family history of DM in two or more generations. We sequenced HNF1A in 27 patients and GCK in seven subjects with asymptomatic mild fasting hyperglycemia. In addition, we calculated MODY probability with MPC. Results We identified 11 mutations in 34 patients (32.3%). We found three novel mutations. In the GCK group, six cases had mutations (85.7%), and their MODY probability on MPC was higher than 50%. In the HNF1A group, five of 27 individuals had mutations (18.5%). The MPC was higher than 75% in 11 subjects (including all five cases with HNF1A mutations). Conclusion Approximately one third of the studied patients have GCK or HNF1A mutations. Inclusion criteria included efficiency in detecting patients with GCK mutations but not for HNF1A mutations (< 20%). MPC was helpful in narrowing the number of candidates for HNF1A screening.
Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Young Adult , Diabetes Mellitus, Type 2 , Hepatocyte Nuclear Factor 1-alpha/genetics , Glucokinase/genetics , Mutation/genetics , Pedigree , Phenotype , Brazil , Cross-Sectional Studies , ProbabilityABSTRACT
Objective To find novel genes related to maturity-onset diabetes of the young(MODY)or novel muta-tions of known MODY related genes and provide the basis for MODY diagnosis. Methods Taking the major clinical features of MODY as screening criteria,we selected four patients from the Endocrine Department of Peking Union Medical College Hospital and prepared their genomic DNA sample for whole exome sequencing.PCR and Sanger se-quencing are used to validate the sequencing results. Results Two novel mutations of the GCK gene and HNF4α gene, c.1348G>T(p.Ala450Thr)and c.758G>A(p.Arg253Gln)were found in two patients. Conclusions These two patients are both MODY patients and this is the first time the novel mutations were found.
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Objective To analyze the clinical characteristics and gene mutations of 56 patients with congenital hyperinsulinism(CHI)and to provide a theoretical basis for clinical diagnosis and treatment of CHI.Methods Fifty-six children who were diagnosed as CHI between February 2002 and January 2016 in Beijing Children's Hospital Affiliated to Capital Medical University were selected as research subjects.A retrospective study was done about the clinical data and the treatment procedures of the 56 patients,such as perinatal conditions,clinical manifestations,laboratory data,treatments,prognosis and so on.Polymerase chain reaction(PCR)-DNA technology or next-generation sequencing technology was used to analyze the CHI relevant genes of the 56 patients.Results Thirty of the 56 patients carried CHI gene mutation.(1)Twenty-three of 56 patients(41.0％)carried ABCC8/KCNJ11 gene mutations:4 of 23 patients carried complex heterozygous mutation,1 of 23 patients carried both ABCC8 and KCNJ11 gene mutation,1 of 23 patients carried maternally inherited ABCC8 gene mutation,12 of 23 patients carried paternally inherited ABCC8 gene mutation,1 of 23 patients carried paternally inherited KCNJ11 gene mutation,3 of 23 patients carried de novo ABCC8 gene mutation,1 of 23 patients had unknown genetic way,19 of 23 patients were treated with Diazoxide,2 of 19 patients were responsive to Diazoxide,7 of 19 patients were unresponsive to Diazoxide and 10 of 19 patients were uncertain to Diazoxide.(2)Five of 56 patients(8.9％)carried GLUD1 gene mutation,4 of 5 patients were treated with Diazoxide and they were all responsive to Diazoxide.(3)One of 56 patients(1.7％)carried de novo GCK gene mutation,responsive to Diazoxide treatment.(4)One of 56 patients(1.7％)carried maternally inherited SLC16A1 gene mutation,responsive to Diazo-xide treatment.Conclusions The ABCC8 gene and GLUD1 gene mutation are the main causative genes of CHI.The GCK gene and SLC16A1 gene mutation are in the minority.Most ABCC8 gene and KCNJ11 gene mutation are unresponsive to Diazoxide treatment.
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La diabetes MODY (Maturity Onset Diabetes of the Young) comprende un grupo heterogéneo de enfermedades monogénicasque se caracterizan por la disfunción de las células β. Se estima que ellas son responsables de 2-5% de los casos de diabetes. Seconocen más de 200 mutaciones en el gen de la glucoquinasa (GCK). En este trabajo se expone el caso de dos hermanas enlas cuales se realizó el diagnóstico de MODY 2 a través del estudio genético, hallándose una mutación del gen de la GCK nodescripto previamente en la bibliografía.
MODY (maturity onset diabetes of the young) includes a heterogeneous group of monogenic diseases which are characterized bydysfunction of beta cells. It accounts for 2-5% of all cases of diabetes. Over 200 mutations in the glucokinase (GCK) gene are known.In this paper we discuss the cases of two sisters in which the diagnosis of MODY 2 was performed by genetic studies, and report thefinding of a mutation in the GCK gene not previously described in the literature.
Subject(s)
Humans , Female , Child , Hyperglycemia , Diabetes Mellitus , Glucokinase/genetics , Mutation/geneticsABSTRACT
HGK is a germinal center kinase (GCK)-Ⅳand is involved in controlling cellular processes, such as cell motility, cy-toskeleton rearrangement, and cell proliferation. HGK is involved in a very complex network of signaling pathways and interactions in-volved in diseases, such as diabetes or cancer. HGK was determined to be highly overexpressed in different types of cancers, such as ovarian cancer, hepatocellular carcinoma, lung cancer, pancreatic cancer, and prostate cancer. Recent findings have shown that HGK is a novel target that may provide insight into new therapies to prevent or even treat many metabolic diseases, such as diabetes or even co-lon cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, or hepatic cancer.