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Page 76 Webb et al. J Transl Genet Genom 2020;4:71-80 I https://doi.org/10.20517/jtgg.2020.11

A wide variety of neurological symptoms is also seen with mt-ARS disorders. Leukoencephalopathy may be
seen with AARS2, DARS2, EARS2, NARS2, PARS2, and WARS2 disorders. Epilepsy may be seen with CARS2,
EARS2, FARS2, NARS2, PARS2, RARS2, TARS2, VARS2, and WARS2 disorders. Peripheral neuropathy is
seen with IARS2 disorder. Sensorineural hearing loss may be seen with HARS2, IARS2, LARS2, MARS2,
[18]
NARS2, and PARS2 disorders .

Pathogenic mutations in GARS, which functions in both the cytosol and mitochondria, may cause autosomal
dominant Charcot-Marie-Tooth disease, type 2D (MIM #601472) or autosomal dominant neuropathy,
[25]
distal hereditary motor, type VA (MIM #600794) . Additionally, a few cases of GARS variants causing
autosomal recessive disease have been reported leading to cardiomyopathy or complex neurological
phenotypes [Table 2]. Pathogenic mutations in KARS may cause autosomal recessive Charcot-Marie-Tooth
disease, recessive intermediate B (MIM #613641) or deafness, autosomal recessive 89 (MIM #613916) [26,27] .
[28]
Interestingly, Ruzzenente et al. recently reported a patient with compound heterozygous KARS variants
leading to impaired mitochondrial translation, but intact cytosolic translation. This patient had symptoms
[28]
of sensorineural deafness, developmental delay, hypotonia, and lactic acidosis . Additional case reports
have described additional various phenotypes for patients with pathogenic KARS mutations including optic
neuropathy, progressive leukoencephalopathy, and cardiomyopathy, among others [29-31] .

Gln
Failure of charging of glutaminyl mt-tRNA (mt-tRNA ) has also been identified to cause disease. The
GatCAB aminoacyl-tRNA amidotransferase complex provides this function and is composed of three
subunits: GATA encoded by QRSL1, GATB encoded by GATB, and GATC encoded by GATC. Patients with
defects in glutaminyl mt-tRNA charging present in infancy with lethal cardiomyopathy and lactic acidosis.
Pathogenic variants have been identified in QRSL1, GATB, and GATC, and all cause autosomal recessive
disease [32,33] .

In addition to mt-ARS genes functioning in mitochondrial translation, there is growing evidence that
mt-ARS proteins have potential non-canonical roles in immune regulation, inflammation, and neuronal
[34]
differentiation . Further work is in progress to further explore the many roles of mt-ARS genes.

MITOCHONDRIAL rRNA MUTATIONS
Mitochondrial 55S ribosomes are composed of two subunits. The small 28S subunit (mtSSU) functions to
catalyze the peptidyl-transferase reaction and the large 39S subunit (mtLSU) functions in mt-mRNA binding
[8]
and decoding . The 28S and 39S mitochondrial ribosome subunits are composed of 12S mt-rRNA (mtSSU)
and 16S mt-rRNA (mtLSU) and ribosomal proteins. Both mt-rRNAs are processed from the polycistronic
heavy strand transcript, which also encodes tRNA and tRNA . Following release of the mature mt-rRNAs
Phe
Val
by endonucleolytic cleavage, assembly of the functional mitoribosome proceeds via a complex process
[35]
involving maturation and processing of mt-rRNAs and association with ribosomal proteins . In addition to
Phe
the 16S mt-rRNA, the large subunit of mammalian ribosomes also include tRNA or tRNA Val[36,37] .
The gene MTRNR1 encodes the mitochondrial 12S ribosomal RNA, and the gene MTRNR2 encodes
the mitochondrial 16S ribosomal RNA. Mutations in MTRNR1 are associated with hearing impairment
[39]
[38]
with or without aminoglycoside exposure. The MTRNR1 mutations m.1555A>G and m.1494C>T
have been described as a cause of maternally inherited deafness in numerous case reports but the
phenotype is variable and not completely penetrant. The identification of a pedigree in which deafness
manifested when the m.1555A>G variant was co-inherited with a loss-of-function SSBP1 variant
[40]
suggests that SSBP1 may be a phenotypic modifier of m.1555A>G-associated deafness . Additional
examples of complex phenotypes involving m.1555A>G include in a pedigree in which the hearing loss
[41]
co-segregated with familial dilated cardiomyopathy due to mutations in MT-ATP6 . Recently, expansion
of the MTRNR1 poly-cytidine tract at m.961 has been reported to be associated with non-ophthalmologic