TMEM126B – Mitochondrial Complex I Deficiency

TMEM126B encodes a mitochondrial complex I assembly factor essential for early peripheral arm formation. Pathogenic biallelic variants in TMEM126B lead to isolated complex I deficiency, manifesting as muscle weakness and exercise intolerance. The inheritance is autosomal recessive, with multiple unrelated families reported. Functional assays in patient fibroblasts demonstrate impaired assembly of the peripheral arm and reduced mature complex I levels. Dietary studies suggest responsive subgroups may benefit from high-fat supplementation. Overall, TMEM126B meets strong clinical validity criteria for mitochondrial complex I deficiency.

In the initial cohort, three adult subjects with progressive exercise-induced myalgia and isolated complex I deficiency carried compound-heterozygous TMEM126B variants, including frameshift and nonsense alleles, confirmed by targeted exome sequencing and fibroblast complementation ([PMID:27374773]). These subjects exhibited severe complex I assembly defects that were fully rescued by lentiviral delivery of wild-type TMEM126B cDNA. No additional phenotypes were observed, and all variants segregated in an autosomal recessive pattern across the reported pedigrees.

Subsequently, six cases from four unrelated families were described with biallelic variants including c.635G>T (p.Gly212Val) and c.401del (p.Asn134IlefsTer2), presenting either pure adult myopathy or severe infantile multisystem disease ([PMID:27374774]). Complexome profiling confirmed TMEM126B as the tenth assembly factor and demonstrated founder effects for two recurrent alleles. Viral rescue and proteomic analyses validated the pathogenicity of these variants.

A palmitic acid responsive patient homozygous for c.635G>T (p.Gly212Val) showed increased muscle endurance on a high-fat diet versus high carbohydrate, accompanied by a 25% rise in maximal OXPHOS capacity in mutant fibroblasts treated with palmitic acid but not oleic acid ([PMID:29093663]). This functional dietary assay offers a potential tool to identify TMEM126B-deficient patients who may benefit clinically from ketogenic interventions.

A recent report identified two novel splicing mutations (c.82-2A>G and c.290dupT) in a patient with Leigh-like syndrome, demonstrating complete exon 2 skipping and partial/complete exon 3 skipping via minigene assays and patient RNA analysis ([PMID:36482121]). These intronic and insertion variants provoke frameshifts and premature termination, causing severe complex I assembly defects in lymphocytes.

Collectively, genetic evidence includes ten probands across five unrelated families with biallelic loss-of-function or missense TMEM126B variants, consistent segregation, and autosomal recessive inheritance. Functional evidence is moderate, encompassing fibroblast complementation, complexome profiling, and dietary rescue assays that concordantly demonstrate impaired assembly and restoration of complex I activity upon wild-type complementation or palmitic acid treatment.

The strong genetic and functional concordance supports a causative role for TMEM126B in mitochondrial complex I deficiency. High-throughput sequencing and proteomic approaches should be integrated in clinical diagnostics, and the palmitic acid responsiveness assay may guide personalized dietary therapy. Key take-home: Autosomal recessive TMEM126B variants disrupt early complex I assembly, leading to exercise intolerance; patient fibroblast assays enable targeted dietary intervention.

References

• American journal of human genetics • 2016 • Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency. PMID:27374773
• American journal of human genetics • 2016 • Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. PMID:27374774
• Frontiers in molecular neuroscience • 2017 • Selection and Characterization of Palmitic Acid Responsive Patients with an OXPHOS Complex I Defect. PMID:29093663
• Journal of human genetics • 2023 • Novel biallelic mutations in TMEM126B cause splicing defects and lead to Leigh-like syndrome with severe complex I deficiency. PMID:36482121

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