Progressive nephropathy associated with mitochondrial tRNA gene mutation.
ABSTRACT Mitochondrial DNA plays a crucial role in oxidative production of energy. Thus, defects in mitochondrial DNA can affect virtually all organ systems. The point mutation A --> G at position 3243 in the mitochondrial tRNAleu(UUR) gene is the cause of several distinct types of mitochondrial cytopathy and several clinical phenotypes, including encephalomyopathy with lactic acidosis and stroke-like episodes and maternally inherited diabetes and deafness. This mutation has been recently described also in association with kidney disease, mainly focal and segmental glomerulosclerosis. At present, little is known about the prevalence of this mitochondrial nephropathy, its clinical course and the pathogenesis of glomerular damage. We describe 2 unrelated patients, who presented with proteinuria and progressed to end-stage renal failure. Other clinical features were short stature, severe headache, hearing loss, diabetes mellitus and hypertrophic cardiomyopathy. The main histological finding was an increased number of abnormal mitochondria in tubular cells and podocytes. Analysis of mitochondrial DNA from leukocytes and urine sediment revealed heteroplasmy for the A3243G mutation in tRNAleu(UUR) gene in both patients. Recognition of the characteristic clinical and histological features of the mitochondrial A3243G mutation-associated glomerulopathy will enable correct diagnosis and better management of a disease which is likely to be underdiagnosed.
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ABSTRACT: Aims. Proteinuria not only is a sign of kidney damage, but also is involved in the progression of renal diseases as an independent pathologic factor. Clinically, glomerular proteinuria is most commonly observed, which relates to structural and functional anomalies in the glomerular filtration barrier. The aim of this paper was to describe the pathogenesis of glomerular proteinuria. Data Sources. Articles on glomerular proteinuria retrieved from Pubmed and MEDLINE in the recent 5 years were reviewed. Results. The new understanding of the roles of glomerular endothelial cells and the glomerular basement membrane (GBM) in the pathogenesis of glomerular proteinuria was gained. The close relationships of slit diaphragm (SD) molecules such as nephrin, podocin, CD2-associated protein (CD2AP), a-actinin-4, transient receptor potential cation channel 6 (TRPC6), Densin and membrane-associated guanylate kinase inverted 1 (MAGI-1), α3β1 integrin, WT1, phospholipase C epsilon-1 (PLCE1), Lmx1b, and MYH9, and mitochondrial disorders and circulating factors in the pathogenesis of glomerular proteinuria were also gradually discovered. Conclusion. Renal proteinuria is a manifestation of glomerular filtration barrier dysfunction. Not only glomerular endothelial cells and GBM, but also the glomerular podocytes and their SDs play an important role in the pathogenesis of glomerular proteinuria.International journal of nephrology. 01/2012; 2012:314251.
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ABSTRACT: In the past 20 years, multiple genetic mutations have been identified in patients with congenital nephrotic syndrome (CNS) and both familial and sporadic focal segmental glomerulosclerosis (FSGS). Characterization of the genetic basis of CNS and FSGS has led to the recognition of the importance of podocyte injury to the development of glomerulosclerosis. Genetic mutations induce injury due to effects on the podocyte's structure, actin cytoskeleton, calcium signaling, and lysosomal and mitochondrial function. Transgenic animal studies have contributed to our understanding of podocyte pathobiology. Podocyte endoplasmic reticulum stress response, cell polarity, and autophagy play a role in maintenance of podocyte health. Further investigations related to the effects of genetic mutations on podocytes may identify new pathways for targeting therapeutics for nephrotic syndrome.Pediatric Nephrology 03/2014; · 2.94 Impact Factor
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ABSTRACT: The prevalence of isolated hearing loss (HL) associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. A single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss.PLoS ONE 01/2012; 7(10):e44054. · 3.53 Impact Factor