Family Phenotypic Heterogeneity Caused by Mitochondrial DNA Mutation A3243G (original) (raw)
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Arquivos Brasileiros de Endocrinologia & Metabologia, 2008
The aim of the present study is to investigate the prevalence of ten described mitochondrial DNA (mtDNA) mutations in patients with type 2 diabetes, and search for new mutations in four mtDNA genes in a subgroup of patients with characteristics of maternally inherited diabetes and deafness (MIDD). These mutations were investigated in 407 type 2 diabetic patients without characteristics of mitochondrial diabetes ("classical" type 2 diabetes group) and in 38 type 2 diabetic patients with characteristics suggestive of MIDD. Through sequencing of four mtDNA genes in MIDD patients, we selected fi ve others potentially pathogenic mutations that were also screened in the remaining patients. Overall, the frequency of the fi fteen analyzed mutations was 36.84% in the MIDD group and 2.45% in the "classical" type 2 diabetes group (p < 0.001). In conclusion, our study reinforces the importance of mtDNA mutations in the pathogenesis of MIDD. (Arq Bras Endocrinol Metab 2008; 52/8:1228-1235)
Diabetes Care, 2011
OBJECTIVEdThe m.3243A.G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare. RESEARCH DESIGN AND METHODSdWe studied a patient presenting with diabetes and deafness who does not carry the m.3243A.G mutation. RESULTSdWe identified a deficiency of respiratory chain complex I in the patient's fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient's somatic tissues. CONCLUSIONSdWe describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mutation is likely favored by the m.14530T.C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability.
A subtype of diabetes mellitus associated with a mutation in the mitochondrial gene
Muscle & Nerve, 1995
Recently, in patients with diabetes and deafness, researchers have identified an A to G transition at position 3243 in transfer ribonucleic aCidLeU(UUR) (3243 base-pair (bp) mutation], originally found in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. To determine the prevalence of diabetic patients with this mutation in Japan, we screened selected cohorts of diabetic patients based upon type of diabetes, family history of diabetes, and age of onset; also screened were 550 unselected cohorts of diabetic patients, without prior information. We identified 5 patients with the 3243-bp mutation, suggesting that approximately 0.9% of diabetic patients have it. However, there were none with this mutation in 250 controls with normal glucose tolerance. We also studied the clinical characteristics and insulin secretory characteristics of diabetic patients with 3243-bp mutation. We propose that diabetes mellitus with 3243-bp mutation is a novel subtype of diabetes mellitus, maternally inherited diabetes, and deafness (MIDD).
Diabetes Research and Clinical Practice, 2003
Diabetes mellitus with the mitochondrial DNA 3243(A Á/G) mutation is reported to represent 0.5 Á/2.8% of the general diabetic population. Since the characterization of diabetes with the mutation is still incomplete, we undertook a nationwide case-finding study of genetically defined patients using questionnaires in Japan. One hundred and thirteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a high prevalence of maternal inheritance of diabetes and deafness, short and thin stature, and showed an early middle-aged onset of diabetes and deafness. Eighty-six percent of the patients required insulin therapy due to the progressive insulin secretory defect. Glucose intolerance of the mothers was associated with an early middle-aged onset of diabetes, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The Abbreviations: MIDD, maternally inherited diabetes mellitus and deafness; GAD, glutamic acid decarboxylase; MODY, maturityonset diabetes of the young; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; JDS, Japan Diabetes Society; IDDM, insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes; WPW, Wolff Á/Parkinson Á/White syndrome; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
Journal of Diabetes and its Complications, 2017
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations in both nuclear and mitochondrial DNA. In fact, mitochondrial DNA (mtDNA) defects are known to be associated with a large spectrum of human diseases and patients might present wide range of clinical features with various combinations. Our study reported a Tunisian family with clinical features of maternally inherited diabetes and deafness (MIDD). Accordingly, we performed a whole mitochondrial genome mutational analysis, results revealed a haplotype composed by "A750G, A1438G, G8860A, T12705, T14766C and T16519C", in homoplasmic state, in the mother and transmitted to her daughter and her son. The patient with MIDD2 and retinopathy presented, in addition to this haplotype associated to the MIDD, two de novo variations including a novel one m.8241 T N G (p. F219C) in MT-CO2 gene and a known one m.13276G N A (p. M314 V) in MT-ND5 gene. The coexistence of these two mutations could explain the retinopathy observed in this patient.
Acta Diabetologica, 2004
In this work, patients having type 2 diabetes mellitus and diabetic mothers were tested for the presence of mitochondrial DNA point mutation A3243G. This mutation is associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), diabetes and deafness. Twenty-two diabetic persons were screened. DNA was isolated from peripheral blood lymphocytes and from swabs of oral mucosa. The mitochondrial DNA point mutation A3243G was detected using PCR-RFLP test. The mutation was detected in oral mucosal DNA of two patients (but not from lymphocyte DNA). One patient was a man with hearing and visual impairments and proteinuria; the other was a woman having proteinuria but no hearing impairment. The mutation was not detectable in oral mucosal DNA from the control persons: 20 diabetic patients having diabetic fathers and 22 healthy, nondiabetic volunteers. The incidence of mitochondrial DNA point mutation A3243G in this study of Croatian diabetic patients is in line with data in the literature.
Neurologia i neurochirurgia polska, 2014
The A3243G mutation is one of the most frequent mutations of mitochondrial DNA. The phenotypic expression of the A3243G mutation is variable and causes a wide range of syndromic and non-syndromic clinical disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is the most frequent syndromic manifestation of the A3243G mutation. Stroke-like episodes seem to be the dominant feature of MELAS. We have investigated the case of a family with A3243G mutation, in which a dominant symptom in three generations was the maternally inherited hearing loss with absence of stroke-like episodes. Besides deafness, we found also other clinical features such as myopathy, neuropathy, migraine, ataxia, short stature, diabetes mellitus, and cardiomyopathy.