Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

Abstract

Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency

“…Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for approximately 23% of childhood respiratory chain deficiency cases [1]. Mitochondrial complex I is composed of 44 structural subunits and over 10 assembly factors, which underscores its diverse clinical manifestations that diverge based on severity and age of onset [2]. The clinical presentations range from infant onset subacute necrotizing encephalomyelopathy (Leigh syndrome [MIM: 256000]) to adult-onset exercise-induced myopathy.…”

Recent Advances in Mitochondrial Disease

“…Following identification of TMEM126B as a complex I assembly factor, two groups reported biallelic mutations in a cohort of undiagnosed complex I-deficient patients. Mutations were identified by either whole-exome sequencing or targeted NGS, and their pathogenicity was validated by blue native polyacrylamide gel electrophoresis and Western blotting of patient tissues (1,77).…”

Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I

“…Indeed, individuals with mutations in TMEM126A primarily present with optic atrophy and most have been identified with homozygous nonsense mutations (Hanein et al, 2009;Meyer et al, 2010). This is in contrast to individuals with TMEM126B mutations who present with adult onset myopathy and all identified cases have at least one missense mutation, suggesting total ablation of TMEM126B may not be compatible with human life (Alston et al, 2016;Sánchez-Caballero et al, 2016b). One possibility is that TMEM126B plays a crucial role in the MCIA complex for ND2-module assembly, while other (unidentified) mitochondrial machineries may be able to compensate for the loss of TMEM126A for ND4-module assembly.…”

“…The MCIA complex is involved in assembly of the ND2 membrane module (Formosa et al, 2020;Guerrero-Castillo et al, 2017). While it has been suggested that TMEM126A may play a compensatory role in patient cells with mutations in TMEM126B (Sánchez-Caballero et al, 2016b), the clinical presentation of the two markedly differ (AROA vs late onset myopathy) (Alston et al, 2016). Nevertheless, a role for TMEM126A in complex I assembly may be implicated given that it was found enriched with the complex I assembly factors DMAC1 (Stroud et al, 2016), TMEM186 and COA1 (Formosa et al, 2020), as well as with the general mitochondrial insertase OXA1L (Thompson et al, 2018).…”