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TMEM126B encodes an early assembly factor critical for the peripheral arm assembly of mitochondrial complex I. Autosomal recessive variants in TMEM126B have been implicated in mitochondrial disease, particularly in complex I deficiency of variable severity. In a 2016 study, six individuals from four unrelated families harbored biallelic TMEM126B variants leading to pure myopathy or early infantile multisystem involvement (PMID:27374774). A separate case report described an adult with isolated exercise intolerance and a homozygous p.Gly212Val missense variant confirmed as pathogenic by fibroblast complementation (PMID:29093663). More recently, novel splice-site and insertion mutations were linked to a Leigh-like syndrome with severe complex I deficiency in lymphocytes (PMID:36482121). Together, these studies establish TMEM126B as a disease gene for mitochondrial complex I deficiency.
All reported cases follow an autosomal recessive inheritance pattern. The initial cohort comprised six probands with either compound heterozygous or homozygous TMEM126B variants, with consistent segregation of alleles in available family members (PMID:27374774). Segregation analyses showed variant co-segregation with disease status in parents as obligate carriers; however, detailed counts of additional affected relatives were limited. A single individual from consanguineous parents manifested exercise intolerance without other systemic features (PMID:29093663). In the Leigh-like case, biallelic intronic and insertion mutations were confirmed to segregate in a recessive manner, supporting pathogenicity (PMID:36482121). No de novo occurrences have been reported.
Across these studies, ten distinct TMEM126B variants have been reported, including missense, frameshift, and splicing changes. Missense variants include c.635G>T (p.Gly212Val) and c.397G>A (p.Asp133Asn), both affecting conserved residues within the transmembrane region (PMID:27374774, PMID:27374773). Loss-of-function alleles encompass frameshift mutations such as c.269del (p.Asn90fs), c.401del (p.Asn134IlefsTer2), and c.585dup (p.Leu196fs), as well as nonsense variants like c.208C>T (p.Gln70Ter) (PMID:27374774, PMID:27374773). An intronic splice-site mutation c.82-2A>G and an exonic insertion c.290dupT were also shown to cause exon skipping and premature truncation in a Leigh-like patient (PMID:36482121). No founder variants have been conclusively identified, though recurring observation of p.Gly212Val suggests potential population enrichment.
Functional studies provide moderate experimental support for TMEM126B pathogenicity. Fibroblast assays demonstrated severely reduced complex I assembly and enzymatic activity in cells with TMEM126B variants, which were rescued by lentiviral re-expression of wild-type cDNA (PMID:27374773, PMID:27374774). Complexome profiling confirmed failure to assemble the peripheral arm module, linking genotype to biochemical phenotype (PMID:27374774). In vitro palmitic acid supplementation increased OXPHOS capacity by 25% in p.Gly212Val fibroblasts, indicating a potential dietary intervention for early assembly defects (PMID:29093663). Complementary minigene splicing assays and RNA analysis in patient lymphocytes validated the impact of splice-site and insertion mutations on transcript integrity (PMID:36482121). These concordant functional data support haploinsufficiency as the underlying mechanism.
Clinically, TMEM126B-related disease spans isolated exercise intolerance, pure myopathy, multisystem involvement, and Leigh-like presentations. Exercise-induced muscle weakness and intolerance are common, reflecting the key role of complex I in high-energy tissues. One patient exhibited chronic renal failure and cardiomyopathy in infancy, underlining variable expressivity (PMID:27374774). The palmitic acid rescue assay offers a rapid tool to predict dietary responsiveness in complex I-deficient patients (PMID:29093663). These observations highlight the importance of integrated genetic and biochemical diagnostics, including exome sequencing and proteomic profiling, to identify TMEM126B variants. Prevalence and carrier frequency remain undefined, warranting broader screening in mitochondrial disease cohorts.
Collectively, the identification of multiple biallelic TMEM126B variants across unrelated families, along with consistent segregation, in vitro complementation, and rescue studies, supports a Strong gene–disease association. Genetic evidence includes six probands with compound heterozygous or homozygous variants and multiple LoF alleles, meeting ClinGen genetic criteria (Strong). Functional assays provide Moderate support, demonstrating disrupted assembly, activity, and dietary rescue. No conflicting data have been reported to date. Future studies should assess variant prevalence, detailed segregation, and long-term outcomes of dietary interventions. Key Take-home: TMEM126B testing and functional assays inform diagnosis and may guide personalized dietary therapy in mitochondrial complex I deficiency.
Gene–Disease AssociationStrongSix probands from four unrelated families with concordant phenotype and functional validation Genetic EvidenceStrongSix probands with biallelic TMEM126B variants, including multiple loss-of-function and missense alleles across four unrelated families Functional EvidenceModerateRescue of complex I activity by wild-type complementation, complexome profiling, and palmitic acid assays demonstrate pathogenic mechanism |