Abstract
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 TMEM126Bfrom
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 carryingTMEM126B 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 TMEM126Bmutations.