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Mitochondrial RNA processing defect caused by a SUPV3L1 mutation in two siblings with a novel neurodegenerative syndrome
Author(s) -
Esveld Selma L.,
Rodenburg Richard J.,
AlMurshedi Fathiya,
AlAjmi Eiman,
AlZuhaibi Sana,
Huynen Martijn A.,
Spelbrink Johannes N.
Publication year - 2022
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12476
Subject(s) - biology , microbiology and biotechnology , mutation , atrophy , proband , exon , genetics , gene
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.