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

K. Svojšová K. Kidd Dita Mušálková T. Kmochová H. Hartmannová K. Hodaňová V. Stránecký V. Barešová Helena Trešlová M. Radina L. Pavlovičová J. Sikora Abbigail Taylor L. Martin A. Sanchez N. Weller Thomas Pinder M. Astley Xiangling Wang Abhijit Dixit S. Korbet Colm Rowan Peter J Conlon K. Soto Afonso Santos Marek Mysliveček J. Zeman Hana Štufková Hana Hansíková K. Tauchmannová Petr Pecina V. Kaplanová M. Vrbacký T. Mráček Örjan Persson Claes M Gustafsson M. Falkenberg M. Živná A. Bleyer Stanislav Kmoch
Aug 2026 · medRxiv · 0 citations
Medicine

TL;DR

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.

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Open access Jul 2026

Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant

Background and Objectives Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD). Methods We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region. Results We identified significant genetic linkage to encephalopathy (chromosome 7q22; LOD = 3.72), and regions suggestive of genetic linkage on chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like episodes. No linkage was identified for diabetes or hearing impairment. Association analysis within the chromosome 7 region identified variant rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10−5), yet no variants reached the proportional significance threshold (5.3 × 10−6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10−3) and IMMP2L (p = 6.4 × 10−3) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds. Discussion The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.

R. Boggan, Theodora-Dafni Michalettou, Y. Ng et al. · 0 citations
Open access Aug 2026

Neonatal mitochondrial encephalopathy due to a splice-altering variant in COX16

COX16 is a nuclear-encoded assembly factor essential for mitochondrial cytochrome c oxidase (complex IV) biogenesis. Only two patients with COX16-related disease have previously been reported. We describe two siblings born to consanguineous parents who presented with neonatal hypotonia, respiratory failure, lactic acidosis and early death. Neuroimaging revealed diffuse white matter abnormalities; neither had cardiac involvement. Muscle and fibroblast studies demonstrated isolated complex IV deficiency. Whole-exome sequencing identified a novel homozygous intronic COX16 variant (c.70-11_70-8del), extremely rare in population databases and observed only in the heterozygous state and predicted to have minimal splicing impact. Reverse transcription-PCR and long-read complementary DNA sequencing confirmed complete exon 2 skipping in patient fibroblasts. Blue native polyacrylamide gel electrophoresis showed defective complex IV assembly. These findings establish the pathogenicity of a splice-altering COX16 variant and expand the genetic and phenotypic spectrum of COX16 -related mitochondrial disease. Our report underscores the importance of transcript-level assays when in silico predictions are inconclusive and highlights the usefulness of integrated genomic and functional approaches.

Nicolas Geoffre, N. Gueguen, Anne-Sophie Guémann et al. · 0 citations
Jul 2026

Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.

Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.

Ismail Gouiza, A. Bouzidi, Meriem Hechmi et al. · 0 citations
Review Open access Aug 2026

Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.

BACKGROUND Variants in the MT-TI gene, which encodes mitochondrial transfer RNA for isoleucine, have been associated with neuromuscular, cardiac, auditory, renal, and metabolic disorders, but their clinical interpretation remains difficult. OBJECTIVE To integrate clinical, familial, heteroplasmy, and functional evidence across the reported MT-TI variant spectrum and clarify its implications for variant interpretation and diagnosis. METHODS We conducted a narrative review of reported MT-TI variants, with detailed comparison of seven representative variants and synthesis of phenotypic, familial, tissue-specific heteroplasmy, and functional findings. RESULTS Evidence was derived mainly from case reports and small pedigrees. Heteroplasmy differed markedly among blood, skeletal muscle, and myocardium, indicating that blood may not represent variant loads in energy-demanding tissues. Reported values generally reflected the lowest observed levels in affected individuals or family-specific boundaries rather than validated pathogenic cutoffs. Functional findings support a staged mechanism involving disturbed transfer RNA processing, structure, stability, or aminoacylation, followed by impaired mitochondrial protein synthesis and respiratory-chain dysfunction. Integrated mechanistic support was limited to a few variants, including m.4295A>G; evidence for most variants remained incomplete or indirect. CONCLUSION Diagnosis requires tissue-informed heteroplasmy assessment integrated with phenotype, maternal family history, and functional evidence. Current treatment is supportive, and proposed reproductive and molecular strategies lack MT-TI-specific clinical-trial evidence.

En-Chi Yuan, Ning Zhang, Haoyu He et al. · 0 citations
Jul 2026

Mitochondrial tRNAGly A10055G mutation contributes to non-syndromic hearing loss: a study of three Han Chinese pedigrees

Abstract Mutations in mitochondrial tRNA (mt-tRNA) genes are associated with non-syndromic hearing loss (NSHL), though their detailed molecular mechanisms and pathogenic potential remain unclear. In this study, we reported three Han Chinese pedigrees exhibiting maternally transmitted NSHL. Mitochondrial genomes from probands were sequenced and compared to revised Cambridge reference sequence (rCRS), followed by phylogenetic analysis to assess pathogenicity. We further established cybrid cell lines to measure mtDNA copy number, ATP levels, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and 8-OHdG, we also screened mutations in nuclear deafness genes including GJB2, GJB3, GJB6, and TRMU. Affected individuals displayed a wide range of age at onset (mean 40.5 years) of deafness. A homoplasmic m.A10055G mutation was identified in the tRNAGly gene, which disrupted a conserved base pair. Compared to controls, mutant cybrids showed significantly reduced mtDNA copy number, ATP, and MMP, along with increased levels of 8-OHdG and ROS, whereas no pathogenic nuclear variants were detected. Collectively, these findings indicated that the m.A10055G mutation contributed to NSHL pathogenesis by impairing mitochondrial functions, most likely through defective tRNA metabolism and by increasing oxidative stress.

Xiao-Xiang Chen, Xiu-Mei He, Yun Li et al. · 0 citations
Case report Open access Aug 2026

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization

The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al. · 0 citations