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Leigh syndrome (LS)/Leigh-like syndrome (LLS) is one of the most common mitochondrial disease subtypes, caused by mutations in either the nuclear or mitochondrial genomes. Here, we identified a novel intronic mutation (c.82-2 A > G) and a novel exonic insertion mutation (c.290dupT) in TMEM126B from a Chinese patient with clinical manifestations of LLS. In silico predictions, minigene splicing assays and patients’ RNA analyses determined that the c.82-2 A > G mutation resulted in complete exon 2 skipping, and the c.290dupT mutation provoked partial and complete exon 3 skipping, leading to translational frameshifts and premature termination. Functional analysis revealed the impaired mitochondrial function in patient-derived lymphocytes due to severe complex I content and assembly defect. Altogether, this is the first report of LLS in a patient carrying mutations in TMEM126B. Our data uncovers the functional effect and the molecular mechanism of the pathogenic variants c.82-2 A > G and c.290dupT, which expands the gene mutation spectrum of LLS and clinical spectrum caused by TMEM126B mutations, and thus help to clinical diagnosis of TMEM126B mutation‐related mitochondrial diseases.

Leigh syndrome (LS) is one of the most common mitochondrial disease subtypes, caused by mutations in either the nuclear or mitochondrial genomes. TMEM126B was identified as a mitochondrial complex I assembly factor. Here, we identified a novel intronic mutation (c.82-2A>G) and a novel exonic insertion mutation (c.290dupT) in TMEM126B from a Chinese patient with clinical manifestations of LS. In silico predictions, minigene splicing assays and patients’ RNA analyses determined that the c.82-2A>G mutation resulted in complete exon 2 skipping, and the c.290dupT mutation provoked partial and complete exon 3 skipping, leading to translational frameshifts and premature termination. Functional analysis revealed the impaired mitochondrial function in patient-derived lymphocytes due to the complex I content and assembly defect. Although TMEM126B mutations have been related to multi-symptoms (exercise intolerance, severe muscle weakness, hyperlactic acidemia, pure myopathy, chronic renal failure and cardiomyopathy), we found the patient carrying these two mutations developed an middle-onset LS. Altogether, this is the first report that the patient carrying TMEM126B mutations was diagnosed with LS. Our data uncover the functional effect and the molecular mechanism of the pathogenic variants c.82-2A>G and c.290dupT, which expand gene mutation spectrum of LS and clinical spectrum caused by TMEM126B mutations.