Nephropathy, Chronic Tubulointerstitial

A number sign (#) is used with this entry because of evidence that chronic tubulointerstitial nephropathy can be caused by a 5656A-G transition in mitochondrial DNA. This adenine is the single noncoding nucleotide separating the structural genes of 2 tRNAs: tRNA (ala) (590000) and tRNA (asn) (590010).

Szabolcs et al. (1994) reported the case of an 8-year-old girl with megaloblastic anemia and severe growth retardation who developed progressive renal insufficiency accompanied by partial Fanconi syndrome. Histologic examination of the renal biopsy disclosed nonspecific chronic tubulointerstitial disease characterized by tubular atrophy and interstitial fibrosis. On ultrastructural examination, tubular cell mitochondria were extremely dysmorphic with prominent variation in size, abnormal arborization, disorientation of the cristae, and osmiophilic electron-dense inclusions. Histochemical stains for mitochondrial enzymes showed focal tubular absence of cytochrome C oxidase (see 516030), a respiratory chain enzyme partially encoded by mtDNA, with preservation of succinate dehydrogenase (see 600857), a respiratory chain enzyme entirely encoded by nuclear DNA. Molecular analysis of mtDNA of kidney and peripheral blood leukocytes by Southern blot and PCR showed a 2.7-kb mtDNA deletion located between nucleotides 9700 and 13700, a common site for mtDNA deletions associated with encephalomyopathies. Szabolcs et al. (1994) suggested that mitochondrial DNA deletions may be an underrecognized cause of idiopathic tubulointerstitial nephropathy in children lacking neurologic or myopathic manifestations.

Zsurka et al. (1997) found distorted mitochondria on renal biopsy of 2 children and a maternal relative with severe progressive tubulointerstitial nephritis. Analysis of mitochondrial DNA showed no major deletion; however, an A-to-G transition was detected at position 5656. This adenine is the single noncoding nucleotide separating the structural genes of 2 tRNAs: tRNA (ala) (590000) and tRNA (asn) (590010). The authors proposed that this mutation may play a causative role in the renal disease of the patients. It was present in all 3 probands but not in 54 controls. The mutation was not known to occur as a natural polymorphism. The A at position 5656 is evolutionarily highly conserved; all known mammalian mtDNA sequences have A in this position.