Prevalence of Japanese dialysis patients with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNALeu(UUR) gene

Yamagata, Kunihiro; Tomida, Chie; Umeyama, Kazuiro; Urakami, Kenichi; Ishizu, Takashi; Hirayama, Kouichi; Gotoh, Michihiro; Iitsuka, Tadashi; Takemura, Katsumi; Kikuchi, Hiroshi; Nakamura, Hideko; Kobayashi, Masaki; Kôyama, Akio

doi:10.1093/ndt/15.3.385

Cited by 15 publications

(15 citation statements)

References 19 publications

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“…In adulthood, the A3243G mutation is so far the unique mtDNA mutation responsible for kidney disease. In two studies of Japanese diabetic patients on regular dialysis, its prevalence reached 0.8 and 5.9%, respectively (40,41). In a French diabetic population, renal involvement of various severities was found in 28% of 54 patients with A3243G mutation after a 12-yr follow-up (22).…”

Section: Discussionmentioning

confidence: 97%

The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

Guéry¹,

Choukroun

Nôël³

et al. 2003

Journal of the American Society of Nephrology

109

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ABSTRACT. The A3243G mutation of the mitochondrial tRNA(Leu) gene has been recently reported in rare patients with focal and segmental glomerulosclerosis (FSGS). However, the full spectrum of systemic and kidney manifestations in adults presenting with this mutation remains poorly defined. Assessment of renal and nonrenal manifestations was performed in nine patients with A3243G mutation and prominent kidney disease diagnosed in adulthood. At first renal evaluation, median age was 35 years. Renal lesions consisted of FSGS (n = 2), tubulointerstitial nephropathy (n = 3), or bilateral enlarged cystic kidneys (n = 1). All but one patient exhibited extrarenal manifestations: deafness (8 of 9) requiring hearing aid in half the cases, diabetes mellitus (3 of 9), neuromuscular involvement (2 of 9), hypertrophic cardiomyopathy (1 of 9), and macular dystrophy (1 of 9). After a median follow-up of 5 yr, five patients progressed to end-stage renal disease between the ages of 15 and 51 years, four being successfully transplanted. Similarly, extrarenal manifestations progressed since all patients had deafness and diabetes (including three posttransplants), while half had neuromuscular, cardiac, or retinal involvement. In the adult patients with A3243G mutation and renal involvement, preexisting deafness is almost consistently found. While FSGS remains the most typical lesion, tubulointerstitial nephropathy or bilateral, enlarged cystic kidneys may also be encountered. In most cases, diabetes mellitus, macular dystrophy, hypertrophic cardiomyopathy, or neuromuscular features occur later in the course of the disease. The severity of the clinical course is heterogeneous, with end-stage renal failure being reached between the second and sixth decades. Renal transplantation may be offered to these patients, despite a high incidence of steroid-induced diabetes mellitus. E-mail: dominique.chauveau@nck.ap-hop-paris.fr

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Section: Discussionmentioning

confidence: 97%

The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

Guéry¹,

Choukroun

Nôël³

et al. 2003

Journal of the American Society of Nephrology

109

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“…The mtDNA 3243A3 G point mutation is regarded as another form of familial FGS. This mutation has been observed in approximately 0.6 to 1.5% of patients with type 2 diabetes mellitus (25,33) and in approximately 16.3/ 100,000 individuals in the general adult population (34). Guillausseau et al (35) reported that 28% of patients with type 2 diabetes mellitus and the mtDNA 3243A3 G point mutation exhibited kidney disease, and renal histologic analyses for three patients who underwent renal biopsies demonstrated FGS.…”

Section: Discussionmentioning

confidence: 99%

“…Age-dependent accumulation of an A3 G transition at mtDNA position 3243 has also been reported (20 -22). Blood cells often exhibit low levels of mutated mtDNA, with mutations such as the common deletion and the 3243A3 G transition (23)(24)(25). In general, glomerular epithelial cells are regarded as terminally differentiated cells that do not proliferate (26 -28).…”

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confidence: 99%

Mitochondrial DNA Mutations in Focal Segmental Glomerulosclerosis Lesions

Yamagata¹,

Muro²,

Usui³

et al. 2002

Journal of the American Society of Nephrology

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ABSTRACT. Glomerular epithelial cells are primary pathogenic sites in focal segmental glomerulosclerosis (FGS) lesions. Glomerular epithelial cells are regarded as terminally differentiated cells that do not proliferate. These characteristics are also noted for neurons and muscular cells, which are major sites of mitochondrial DNA (mtDNA) mutation accumulation. Screening for mtDNA mutations was performed with renal biopsy specimens from patients with primary FGS and patients with IgA nephropathy (as subjects with secondary FGS and as control subjects). mtDNA extracted from kidney biopsy specimens was amplified with appropriate primer pairs for study of the mtDNA point mutations 3243A→G, 3271T→C, 8344A→G, and 8993T→G/C, as well as the common deletion (a 4977-bp deletion spanning mtDNA nucleotide pairs 8469 to 13447). In situ amplification of both total mtDNA and the common deletion was also performed. Two patients with FGS demonstrated the 3243A→G point mutation; 12 patients with FGS and seven patients with IgA nephropathy accompanied by glomerulosclerotic lesions exhibited the common deletion in their kidney tissue. No patient demonstrated the mtDNA mutations 3271T→C, 8344A→G, or 8993T→G/C. The degree of heteroplasmy for the 3243A→G point mutation was >85%; however, the heteroplasmy for the common deletion was <1%. As determined with in situ PCR, normal mtDNA was mainly distributed in the tubular epithelium and mtDNA with the common deletion was mainly distributed among glomerular epithelial cells. In conclusion, it is suggested that mtDNA mutations are distributed in glomerular epithelial cells among some patients with primary FGS or secondary FGS with IgA nephropathy. These mutations may be related to glomerular epithelial cell damage.

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“…In the present study, one patient (case 1), who had the A3243G mutation at a relatively high percentage in mtDNA in leukocytes, had SNHL and cardiomyopathy but not DM. Cardiac involvement has been reported in patients with the mutation and DM/SNHL (Shiotani et al 1998;Yamagata et al 2000). Another organ that has been relatively frequently reported to be involved in patients with the mutation is the kidney (Cheong et al 1999;Nakamura et al 1999;van den Ouweland et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent work showed that the identical mutation is also causative for maternally inherited diabetes associated with deafness van den Ouweland et al 1992van den Ouweland et al , 1994, and the name MIDD (maternally inherited diabetes and deafness) was proposed for this syndrome (van den Ouweland et al 1994(van den Ouweland et al , 1995. Furthermore, the A3243G mutation was shown to be a cause of an overlapping syndrome of MERRF (myoclonic epilepsy with ragged-red fibers) and PEO (progressive external ophthalmoplegia) (Verma et al 1996), PEO (Koga et al 2000;Pang et al 1999), Kearns-Sayre syndrome (Pang et al 1999), Leigh syndrome (Koga et al 2000), progressive nondiabetic kidney disease (Cheong et al 1999;Jansen et al 1997), and cardiac diseases (Shiotani et al 1998;Yamagata et al 2000). Majamaa et al (1998) studied an adult population of 245,201 individuals, and screened for the A3243G mutation in 480 selected subjects who had one or more of following diseases: diabetes mellitus (DM), sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia.…”

Section: Introductionmentioning

confidence: 99%

Frequency and clinical features of patients with sensorineural hearing loss associated with the A3243G mutation of the mitochondrial DNA in otorhinolaryngic clinics

et al. 2001

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The A3243G mutation of the mitochondrial gene is a cause of maternally inherited diabetes and deafness. The aim of this study was to evaluate the frequency and clinical features of this mutation in patients with sensorineural hearing loss (SNHL) in otorhinolaryngic clinics. The frequency of the A3243G mutation in 230 patients with SNHL was 1.74% (4/230). Three of the four patients had diabetes mellitus (DM) and were already aware that they had the mutation. The other had cardiomyopathy but not DM, and proved to have the mutation in this study. The frequency of the mutation was 12.9% (4/31) in patients with a family history of possible maternal inheritance of SNHL, 10.3% (3/29) in patients with DM, and 50% (3/6) in patients with both. The age of onset of SNHL in these patients and their families was between their teens and their forties. The chance of diagnosing the A3243G mutation in patients with SNHL in otorhinolaryngic clinics is probably less than 1%. Association of DM, cardiomyopathy, a family history of possible maternal inheritance of SNHL, and an onset of SNHL between the teens and the forties are signs suggesting the mutation. These signs provide us with a reason for genetic testing for the mutation.

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Prevalence of Japanese dialysis patients with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNALeu(UUR) gene

Abstract: We found that a mitochondrial gene mutation at nucleotide 3243 was present in one dialysis patient with NIDDM and deafness. The prevalence of this mutation was found to be below 1% in diabetic end-stage renal disease patients in Japan.

Cited by 15 publications

References 19 publications

The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

Mitochondrial DNA Mutations in Focal Segmental Glomerulosclerosis Lesions

Frequency and clinical features of patients with sensorineural hearing loss associated with the A3243G mutation of the mitochondrial DNA in otorhinolaryngic clinics

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