Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure—Implications for Mitochondrial Genetic Testing in Nephrology

Abstract

An adult with kidney failure had compound‐heterozygous TMEM126B variants causing mitochondrial complex I deficiency. This expands TMEM126B to mitochondrial nephropathy and supports including mitochondrial genes in renal genetic testing.

Mitochondrial disorders comprise a heterogeneous group of genetic diseases caused by defects in oxidative phosphorylation [1]. Although neurological and muscular manifestations predominate, mitochondrial dysfunction can result in renal disease, often manifesting as tubulointerstitial nephritis, tubular dysfunction, and progressive kidney disease [1, 2].

TMEM126B (OMIM 615533) encodes an inner mitochondrial membrane protein, anchoring assembly intermediates for complex I biogenesis (Figure 1A) [3]. Biallelic pathogenic TMEM126B variants are associated with mitochondrial complex I deficiency (OMIM 618250), typically presenting with exercise intolerance, muscle weakness, and hyperlactatemia. A single infantile case with multi‐systemic involvement that included renal failure with renal tubular acidosis has been reported (Figure 1B) [3, 4].

FIGURE 1.

Mitochondrial Nephropathy Overview and Clinical Spectrum of TMEM126B Disorders. (A) (Top) Mitochondrial roles in kidney health. (Bottom) Nuclear‐ and mitochondrial‐encoded genes associated with renal phenotypes [1]. (B) Clinical features of the proband (left) compared to previously reported cases of TMEM126B‐related complex I deficiency (right). (C) TMEM126B variants: ClinVar variants gray; proband variants red. Proband variants: C.241del (p.Thr81Glnfs*24; truncating) and c.635G>T (p.Gly212Val; within a predicted inner mitochondrial membrane helix). Inset: DeepTMHMM topology (inner membrane in orange). AlphaFold AF‐Q8IUX1‐F1‐v4 confidence: Mean pLDDT 80.9 (high); Gly212 pLDDT 94.7 (very high). ChimeraX model of G212V shows steric clashes (purple) and H‐bonds (blue).

We report a 24‐year‐old man who presented at age 21 with elevated serum creatinine and hypertension. His creatinine rose to 213 μmol/L over 1 year and then to 1000 μmol/L within 3 months, despite a course of high‐dose prednisone. Ultrasound showed echogenic kidneys; a kidney biopsy revealed active and chronic tubulointerstitial nephritis with cortical scarring and no active glomerulonephritis. Electron microscopy of tubular epithelial cells showed variable mitochondrial morphology without disorganized cristae or paracrystalline inclusions. Phenotype‐driven exome sequencing identified compound heterozygous TMEM126B variants—c.241del, p.(Thr81Glnfs*24) and c.635G>T, p.(Gly212Val)—confirmed to be in trans by parental testing. The family is non‐consanguineous without a history of renal disease. The p.(Thr81Glnfs*24) variant is novel, while the p.Gly212Val variant has been reported earlier and disrupts the C‐terminal transmembrane domain, leading to impaired complex I assembly (Figure 1C) [3]. Post hoc phenotyping revealed persistent exercise intolerance without neurological deficits. Metabolic evaluation revealed elevated urinary lactate (256 mmol/mol creatinine) and malate (11 mmol/mol creatinine), along with markedly increased plasma growth differentiation factor 15 (GDF15; 4287 pg/mL), consistent with mitochondrial dysfunction. GDF15 is a biomarker for mitochondrial disease but may be elevated in chronic kidney disease and systemic stress conditions [5]. The renal pathology reflects the high‐energy demands of proximal tubular epithelial cells, where complex I deficiency impairs ATP production and promotes tubular injury. Following the molecular diagnosis, treatment with mitochondrial supplementation (coenzyme Q10, L‐carnitine, and B‐vitamins) was initiated, and a disease‐adapted anesthesia protocol was implemented during living‐donor kidney transplantation. GDF15 levels remained elevated post‐transplant, supporting the presence of mitochondrial dysfunction despite restored kidney function.

Renal involvement can be an early feature in mitochondrial disease, occurring in up to 57% of genetically confirmed cases [2]. Despite the utility of exome sequencing, standard nephrology panels often exclude mitochondrial genes like TMEM126B, contributing to under‐recognition. Clinical exome‐based tests often omit deliberate mtDNA capture, providing inconsistent off‐target coverage. In exome‐ or panel‐negative patients with mitochondrial‐compatible features or unexplained kidney failure, mtDNA coverage should be assessed; if inadequate, dedicated mtDNA sequencing or genome sequencing should be considered. Pathogenic variants in both mitochondrial and nuclear genes affecting all complexes of the mitochondrial respiratory chain, except for complex II and cytochrome c, have been implicated in mitochondrial nephropathy (Figure 1A).

This case expands the phenotype of TMEM126B‐related disease to adult‐onset primary renal failure with tubulointerstitial nephritis, supports the inclusion of mitochondrial genes in renal genetic testing strategies, and illustrates how a genetic diagnosis can inform perioperative management and adjunctive therapy.

Ethics Statement

McGill University Health Centre Research Ethics Board (20239387). Written informed consent was obtained in accordance with the Declaration of Helsinki.

Conflicts of Interest

The authors declare no conflicts of interest.

Sentell Z. T., Cheung A. C. T., Russo F., et al., “Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure—Implications for Mitochondrial Genetic Testing in Nephrology,” Clinical Genetics 109, no. 1 (2026): 206–208, 10.1111/cge.70073.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.