Autosomal recessive pathogenic MSTO1 variants in hereditary optic atrophy

Abstract

Gerber et al report 2 autosomal recessive pathogenic Misato homolog 1 (MSTO1) variants causing hereditary optic atrophy and raise concerns about a previously identified dominant variant of MSTO1 by Gal et al (2017).

Answer to Gerber et al. “Autosomal recessive pathogenic MSTO1 variants in hereditary optic atrophy”

“…The correspondence article by Gerber et al. “ Autosomal recessive pathogenic MSTO1 variants in hereditary optic atrophy ” (Gerber et al , 2023 ) is questioning the disease relevance of the c.22G>A p. (p.(Val8Met) or V8M) variant in MSTO1 we reported in 2017. They identified the same rare variant in 16/49 patients having optic neuropathy in heterozygous form.…”

“…We resequenced both Patient 1 (I/1) and 2 (II/1) samples with our original primer that does not discriminate between MSTO1 and MSTO2p , and also with the MSTO1 and MSTO2p ‐specific primers introduced by Gerber et al ( 2023 ). Using the original primers, the patients again presented heterozygous MSTO1 mutation but using the new primers they showed no mutation in MSTO1 and homozygous mutation in MSTO2p (Fig 1 ).…”

“…Database information ( https://www.ncbi.nlm.nih.gov/snp/rs11264409 ) and results by Gerber et al ( 2023 ) indicated that the present mutation in MSTO2p is common and likely benign. However, it is worth noting that both patients 1 (I/1) and 2 (II/1) in our original paper Gal et al ( 2017 ) showed decreased MSTO1 mRNA and protein levels (fig 1E and F) and a mitochondrial phenotype (figs 2 and 3).…”

MSTO1 is a cytoplasmic pro‐mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans

“…Editors received a Correspondence article in April 2022, which was revised and published in July 2023 (Gerber et al , 2023 ). This Correspondence article raised concerns about an MSTO1 gene mutation that was identified and reported to be pathogenic in this manuscript, suggesting that the reported patient‐derived mutation is originated from a pseudogene MSTOP2 and not the protein‐coding gene MSTO1.…”