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

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Complex I deficiency is the most frequent biochemical phenotype in mitochondrial disease, often linked to genetic and clinical heterogeneity.
• Despite advances in massively parallel sequencing (MPS) and whole-exome sequencing (WES), many individuals remain undiagnosed, potentially due to mutations in uncharacterized genes.

Observation:

• Complexome profiling identified TMEM126B as a component of the mitochondrial complex I assembly machinery.
• This study details six cases from four families with biallelic TMEM126B variants (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]).

Findings:

• Functional evidence supports the pathogenicity of TMEM126B variants, with founder effects noted for both.
• TMEM126B defects cause complex I deficiency, presenting as adult-onset myopathy or severe infantile multisystem disease (renal failure, cardiomyopathy).
• TMEM126B is confirmed as the tenth complex I assembly factor implicated in human disease.

Implications:

• This research validates the combined use of genome-wide sequencing and proteomics for characterizing novel disease-associated genes.
• It expands the genetic landscape of mitochondrial complex I deficiency and provides a molecular basis for affected individuals.