The importance of the nuclear background on the phenotypic signature caused by the MELAS m.1630 A>G variant.

Dear Editor,

We appreciate the Letter to the Editor by Dr. Finsterer [1] in response to our publication in Molecular Genetics and Metabolism “The nuclear background influences the penetrance of the near-homoplasmic m.1630A>G variant in a symptomatic proband and asymptomatic mother” [2].

Though the heteroplasmic threshold concept explains most MELAS symptomology, some patients with high heteroplasmy are asymptomatic, suggesting that unknown factors could modulate the variant's penetrance and its phenotypic expression [[2], [3], [4]]. With only 13 proteins encoded by the mitochondrial genome, the nuclear genome contributes to mitochondrial functions via 1158 proteins [5].

The pathogenicity of the m.1630 A>G variant was demonstrated in previous studies [3,4]. The role of the nonsense VARS2 variant as a nuclear modifier is congruent with its sole expression in the proband, and removal of two-third of the VARS2 protein reducing the valine charge of the mutated mt-tRNAval. Although whole genome sequencing could reveal additional variants, the majority of pathogenic mutations are found in coding regions [6]. The differential chromatin landscape between the proband and her mother lends credence to the idea of the nuclear epigenomics modulating MELAS symptomology.

Since the mother's phenotype was reported in the original 2011 study [3], we only took detailed history and performed non-invasive tests. Over the last nine years, she remains asymptomatic with consistent higher levels of heteroplasmy in blood, urine and fibroblasts than her daughter [2,3].

The proband has not taken antiepileptic drugs for many years and at the time of the skin biopsy, which was performed prior to her kidney transplant, making the study of immunosuppressants irrelevant.

No Institutional Review Board responsible to protect the rights and welfare of human research subjects would approve measuring heteroplasmy in multiple affected organs, which could only be performed on autoptic tissues. To this day, the proband and her mother remain alive.

Conflict of interest

There are no conflict of interest to disclose.

Funding

This work was funded by the NIH National Institute of Neurological Disorders and Stroke [NS085282 to AC].