Whole-Exome Sequencing Identifies a Novel POLG Frameshift Variant in an Adult Patient Presenting with Progressive External Ophthalmoplegia and Mitochondrial DNA Depletion.

Justin Kurtz,William C Copeland,Mahesh Mansukhani,Joseph Americo Fernandes,Ali B Naini,Mohnish Suri

doi:10.1155/2021/9969071

Abstract

Mitochondrial DNA (mtDNA) depletion syndromes are a group of autosomal recessive disorders associated with a spectrum of clinical diseases, which include progressive external ophthalmoplegia (PEO). They are caused by variants in nuclear DNA (nDNA) encoded genes, and the gene that encodes for mtDNA polymerase gamma (POLG) is commonly involved. A splice-site mutation in POLG, c.3104+3A > T, was previously identified in three families with findings of PEO, and studies demonstrated this variant to result in skipping of exon 19. Here, we report a 57-year-old female who presented with ophthalmoplegia, ptosis, muscle weakness, and exercise intolerance with a subsequent muscle biopsy demonstrating mitochondrial myopathy on histopathologic evaluation and multiple mtDNA deletions by southern blot analysis. Whole-exome sequencing identified the previously characterized c. 3104+3A > T splice-site mutation in compound heterozygosity with a novel frameshift variant, p.Gly23Serfs∗236 (c.67_88del). mtDNA copy number analysis performed on the patient's muscle showed mtDNA depletion, as expected in a patient with biallelic pathogenic mutations in POLG. This is the first reported case with POLG p.Gly23Serfs∗236, discovered in a patient presenting with features of PEO.

Highlights

Mitochondrial DNA depletion syndromes (MDSs) are a diverse group of autosomal recessive disorders due to mutations in nuclear encoded genes [1]. ey present with a broad phenotypic spectrum with disease manifesting in single or multiple organs, including the muscle, liver, brain, and kidney [2]
E rate and timing of Mitochondrial DNA (mtDNA) synthesis is determined by the energy requirement of a cell [4]. mtDNA replication is independent of the cell cycle, but deoxyribonucleoside triphosphates (dNTPs) are only formed by the de novo pathway during the S-phase of cell division [2]
No additional relevant variants were identified on whole exome sequencing, including in other genes associated with progressive external ophthalmoplegia (PEO) (POLG2, OPA, ANT1, TWNK, RRM2B, DNA2, TYMP, DGUOK, TK2, MGM1, and RNASEH1)

Summary

Introduction

Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a diverse group of autosomal recessive disorders due to mutations in nuclear encoded genes [1]. ey present with a broad phenotypic spectrum with disease manifesting in single or multiple organs, including the muscle, liver, brain, and kidney [2]. MtDNA depletion occurs when synthesis is insufficient to compensate for mtDNA turnover and segregation during cell division. It is caused by defects in genes involved in mtDNA replication or in genes involved in maintaining the pool of deoxyribonucleoside triphosphates (dNTPs) via the salvage pathway [2]. Genes involved in the salvage pathway include TK2, DGUOK, SUCLA2, SUCLG1, RRM2B, and TYMP, and defects in any of these genes may result in mtDNA depletion due to an insufficient pool of dNTPs [2]. DNA polymerase gamma is the only known polymerase involved in the replication and maintenance of mtDNA in humans [6] It is composed of two subunits encoded by nuclear genes (POLG and POLG2). POLG2 at chromosomal locus 17q24.1 encodes an accessory subunit [7]. e C10orf gene encodes a DNA helicase (twinkle protein), which is essential for mtDNA replication [3]

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Conclusion