Recurrent Single-Nucleotide Insertions in the Mitochondrial Second Light-Strand Promoter Cause Tubulointerstitial Kidney Disease

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Abstract Introduction Mitochondrial DNA (mtDNA) is not routinely analyzed in inherited kidney disease. We evaluated mtDNA variation in families who remained genetically unresolved despite extensive testing. Methods We reviewed pedigrees from the Wake Forest–Charles University Rare Inherited Kidney Disease Registry to identify genetically unresolved families with suspected maternal inheritance, performed mtDNA genotyping, clinically characterized variant carriers, and functionally evaluated disease-associated mitochondrial variants. Results Among 33 families with evidence of maternal inheritance, 18 (55%) carried one of seven disease-associated mtDNA variant types, including homoplasmic recurrent single-nucleotide insertions in the second light-strand promoter (LSP2; 9 families), novel MT-TW and MT-TL2 variants (2 and 1 families, respectively), and previously reported MT-TF and heteroplasmic MT-ND5 variant (5 and 1 families, respectively). In 16 families, variants occurred on distinct haplotypes, consistent with independent mutational events and rapid enrichment to homoplasmy across generations. Maternal transmission was strongly supported, with below-normal kidney function observed in 54/60 (90%) offspring of affected mothers versus 1/17 (6%) offspring of affected fathers (p = 1.23 × 10 ⁻11 ). Pathogenicity was further supported by predicted deleterious structural effects and functional evidence of impaired mitochondrial transcription and translation, respiratory chain deficiency, and CoQ10 depletion. Affected individuals predominantly presented with chronic tubulointerstitial kidney disease, occasionally accompanied by gout and only sporadically with extrarenal manifestations. The rate of kidney disease progression appeared to vary both between and within families. Overall, 109/119 genetically affected individuals or obligate at-risk carriers were clinically affected; most unaffected carriers were younger than 45 years of age. Clinical status was unavailable for an additional 66 obligate at-risk carriers. Conclusions These findings establish the physiological relevance of the LSP2 promoter, support routine assessment of the mitochondrial genome in inherited kidney disease, and highlight mtDNA variants as an important cause of familial and sporadic tubulointerstitial kidney disease of previously unexplained etiology. Lay Summary Many inherited kidney diseases remain unexplained because routine genetic testing focuses on genes in the cell nucleus and does not examine mitochondrial DNA—the small genome in the cell’s energy-providing mitochondria, inherited only from the mother. We studied 33 families with chronic kidney disease whose family histories suggested maternal inheritance and identified disease-causing mitochondrial DNA variants in 18 (55%). Nine families carried variants in LSP2, a recently discovered mitochondrial regulatory element, highlighting its importance in normal mitochondrial function and disease. Others carried pathogenic variants in mitochondrial tRNA genes required for mitochondrial protein synthesis. Laboratory studies showed that these variants impair mitochondrial energy conversion. In all families, the predominant manifestation was slowly progressive kidney disease, sometimes leading to dialysis or kidney transplantation. These findings identify pathogenic mitochondrial DNA variants as an underrecognized cause of inherited kidney disease and support the inclusion of mitochondrial DNA analysis in routine genetic testing.

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