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Page 398 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

onset compared to multiple deletion syndromes. For example, TK2-induced mtDNA depletion usually
presents before the age of two years with myopathy, feeding difficulty, hypotonia, and within a few years
respiratory failure [133] . Multiple deletions induced by TK-2 presents later in life with CPEO and proximal
muscle weakness [134] . DGUOK is involved in the purine nucleoside salvage pathway [135] . Patients with
variants in DGUOK producing mtDNA depletion present with early onset liver dysfunction and subsequent
hepatic failure with co-morbid neurodevelopment delay, abnormal eye movements, and hypotonia [136] .
Variants in the DGUOK inducing mtDNA deletions produce disease with adult onset CPEO, myopathy,
and Parkinsonism [137] . Both SUCLA1 and SUCLG1 have similar phenotypes with infantile onset and
mtDNA depletion [138] . The protein products are involved in the citric acid cycle and stabilize enzymes
involved in mtDNA nucleotide pools. Phenotypically, SUCLA1/SUCLG1 variants induce early childhood
hypotonia and subsequently develop muscle atrophy with psychomotor delay. Early patient death occurs
in the SUCLG1 variants, but those with the SUCLA1 variants survive into their twenties. ABAT is the
main enzyme responsible for catabolism of the neurotransmitter gamma-aminobutyric acid and regulates
mitochondrial nucleoside salvage. Variants in ABAT induces infantile spasms, significant developmental
delay and hypotonia, and mtDNA depletion [139] . SAMDH1 is a triphosphohydrolase converting dNTPs
to deoxynucleosides and interfaces with DGUOK to cause mtDNA depletion [140] . Thus far, pathological
variants in SAMDH1 have not been described.

Variants in ribonucleotide reductase, p53-R2 subunit (RRM2B) can cause mtDNA depletion and severe
neonatal/infantile myopathy with some patients developing tubulopathy, seizures, and respiratory
compromise with death before one year of age [141,142] . A milder adult onset type with mtDNA deletions
presents with CPEO [143] . RRM2B is the main regulator of nucleotide pools in the cytoplasm and is likely key
in maintaining dNTP pools for mtDNA synthesis [144] . The cytoplasmic enzyme thymidine phosphorylase
encoded by TYMP regulates pyrimidine deoxyribonuclesidases, thymidine, and deoxyuridine. Loss of
TYMP function induces systemic accumulation of thymidine and deoxyuracil in serum and tissues
with changes in mtDNA stability and, consequently, the mitochondrial syndrome of mitochondrial
neurogastrointestinal encephalopathy (MNGIE) [145,146] . Both mtDNA multiple deletions and mtDNA
depletion have been described and related to region of organ dysfunction within the GI tract, the small
intestine with depletion, and upper GI tract multiple deletions [147] . The onset of MNGIE is late adolescence,
but it can occur at any age (range 5 months to 35 years) [147] . The cardinal features of MNGIE are ptosis,
ophthalmoparesis, leukoencephalopathy, peripheral neuropathy, and severe gastrointestinal dysmotility
with cachexia [Table 1].

Mitochondrial transcription
The mitochondrial genome has 22 genes for tRNA needed for transcription within the IMM anchored
nucleoid. Transcription of mRNA occurs from both heavy and light strands of mtDNA as large
polycistronic precursor mRNA molecules from each strand. Historically, each strand of the mtDNA duplex
is labeled by the number of guanine nucleotides (H-strand for heavy) and cytosine residues (L-strand for
light) that correlated with buoyant density. Both strands express mtDNA genes differentially, the H-strand
consists of 12 of the ETC subunits and 2 of the tRNA genes, while the L-strand produces the other mtDNA
[5]
genes . There are three essential components of transcription initiation, mitochondrial transcription
factor A (TFAM) and B (TFB2M), and the single mitochondrial RNA polymerase (POLRMT). Initiation
of transcription begins by TFAM binding just 10-15 base pairs upstream from the start site, PSP on the
L-strand, and HSP 1 promoter site with unwinding of the DNA [148] . Then, TFAM attracts POLRMT and
TFB2M, and subsequently both of the latter bind to TFAM [149-151] . Both strands of mtDNA are transcribed
simultaneously with termination performed by the mitochondrial termination factor 1 (MTERF1) [152] . The
mechanism of how MTERF1 terminates transcription of the polycistronic strand remains unclear, but data
indicate that it actively terminates L-strand transcription, with indirect stoppage of the H-strand [153] .