Introduction
Leigh syndrome (LS, MIM 256000) is the most prevalent childhood-onset
mitochondrial disease, with neurodegenerative disorders as its most
distinctive feature (Rahman et al., 1996). LS has a prevalence of
approximately 1:40,000 and is highly genetically heterogeneous,
primarily with impaired mitochondrial energy production (Darin et al.,
2001). LS exhibits several different modes of inheritance (X-linked,
autosomal or maternal). To data, more than 75 causing genes including
both mitochondrial and nuclear genes have been identified (Schubert
Baldo & Vilarinho, 2020). Although defects in each of the five
oxidative phosphorylation system (OXPHOS) complexes have been observed
in LS patients (Lake et al., 2016), nearly one-third of LS cases are
related to complex I deficiency. Mitochondrial complex I is essential
for aerobic respiratory and is located in the first of the mitochondrial
oxidative respiratory chain. It oxidizes NADH, which reduces ubiquinone
and transports protons through the inner mitochondrial membrane,
resulting in proton driving force (Hirst, 2013). The complete assembly
of complex I requires at least 45 subunits and 15 assembly factors, each
of which can lead to mitochondrial complex I disruption and ultimately
cause diverse human diseases including neurodegenerative diseases,
aging, mitochondrial disorder and etc (Formosa et al., 2018; Mimaki et
al., 2012; Schapira, 1993; Tinker et al., 2021).
TMEM126B (MIM 615533) is a 7968-bp gene containing five exons
that encodes a component of mitochondrial complex I intermediate
assembly (MCIA) complex, which is required for assembly of complex I but
is not part of the mature complex (Heide et al., 2012). Mutations inTMEM126B would cause an isolated mitochondrial complex I
deficiency and result in various clinical phenotypes such as exercise
intolerance, muscle weakness, hyperlactic acidemia, hypertrophic
cardiomyopathy and renal tubular acidosis (Alston et al., 2016;
Sánchez-Caballero et al., 2016; Theunissen et al., 2017). To date, ten
patients with a total of four mutations in TMEM126B have been
reported worldwide, but all patients reported had a normal in
neurological presentation (Alston et al., 2016; Sánchez-Caballero et
al., 2016; Theunissen et al., 2017). Notably, the genetic spectrum of
the TMEM126B mutations in China remains unclear.
In this study, using next-generation sequencing in a Chinese patient
manifested with LS, we identified
two novel heterozygous mutations
of TMEM126B (c.82-2A>G and c.290dupT).
Bioinformatics analysis and functional assays revealed that
c.82-2A>G mutation
caused complete exon 2 skipping and c.290dupT induced partial and
complete exon 3 skipping.
Patient-derived lymphoblastoid cells
carrying biallelic mutations
exhibited complex I content and
assembly defect and mitochondrial dysfunction. Our findings
uncovered the functional effect
and the molecular mechanism of the pathogenic TMEM126B variants
c.82-2A>G and c.290dupT, which not only expand the
gene mutation spectrum of LS, but
also expand the clinical spectrum caused by TMEM126B mutations.