SUPV3L1 encodes a helicase that is mainly localized in the mitochondria. It has been shown in vitro to possess both
double-stranded RNA and
DNA unwinding activity that is
ATP-dependent. Here we report the first two patients for this gene who presented with a homozygous preliminary stop
codon resulting in a C-terminal truncation of the SUPV3L1
protein. They presented with a characteristic phenotype of neurodegenerative nature with progressive
spastic paraparesis, growth restriction,
hypopigmentation, and predisposition to
autoimmune disease. Ophthalmological examination showed severe
photophobia with corneal erosions,
optic atrophy, and
pigmentary retinopathy, while neuroimaging showed
atrophy of the optic chiasm and the pons with calcification of putamina, with intermittent and mild elevation of
lactate. We show that the
amino acids that are eliminated by the preliminary stop
codon are highly conserved and are predicted to form an amphipathic helix. To investigate if the mutation causes
mitochondrial dysfunction, we examined fibroblasts of the proband. We observed very low expression of the truncated
protein, a reduction in the mature ND6
mRNA species as well as the accumulation of
double-stranded RNA. Lentiviral complementation with the full-length SUPV3L1
cDNA partly restored the observed
RNA phenotypes, supporting that the SUPV3L1 mutation in these patients is pathogenic and the cause of the disease.