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 x 10e-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.
Funding Information
  • Ministry of Education, Youth and Sports of the Czech Republic (MULTIOMICS_CZ (Programme Johannes Amos Comenius, Ministry of Education, Youth and Sports of the Czech Republic,//ID Project CZ.02.01.01/00/23_020/0008540) - Co-funded by the European Union)
  • Ministry of Education, Youth and Sports of the Czech Republic (National Institute for Treatment of Metabolic and Cardiovascular Diseases (CarDia; LX22NPO5104) - Co-funded by the European Union)
  • Ministry of Education, Youth and Sports of the Czech Republic (INTER-EXCELLENCE II grant LUAUS24087)
  • Ministry of Education, Youth and Sports of the Czech Republic (National Center for Medical Genomics (LM2023067))
  • Charles University Grant Agency (GAUK 38226)
  • Agency for Health Research of the Czech Republic (NW26-07-00090)
  • Agency for Health Research of the Czech Republic (NU22-01-00499)
  • Charles University in Prague (UNCE/24/MED/022)
  • Charles University in Prague (Cooperatio 207040-1 Pediatrics)
  • General Faculty Hospital in Prague (RVO-VFN-64165)
  • Czech Academy of Sciences, Institute of Physiology (RVO 67985823)
  • Carlos Slim Health Foundation
  • Black Brogan Foundation
  • Rassmuss Foundation
  • Critical Path Institute US Food and Drug Administration Contract (75F40124C00106)
  • CKD Biomarkers Consortium Pilot and Feasibility Studies Program funded by NIH-NIDDK (U01 DK103225)
  • Soli Deo Gloria
  • Swedish Research Council (2025-00932)
  • Swedish Research Council (2025-01111)
  • Knut and Alice Wallenberg Foundation