De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans

Abstract

Defects in the mitochondrial genome (mitochondrial DNA (mtDNA)) are associated with both congenital and acquired disorders in humans. Nuclear-encoded DNA polymerase subunit gamma (POLG) plays an important role in mtDNA replication, and proofreading and mutations in POLG have been linked with increased mtDNA deletions. SSBP1 is also a crucial gene for mtDNA replication. Here, we describe a patient diagnosed with Pearson syndrome with large mtDNA deletions that were not detected in the somatic cells of the mother. Exome sequencing was used to evaluate the nuclear factors associated with the patient and his family, which revealed a paternal POLG mutation (c.868C > T) and a maternal SSBP1 mutation (c.320G > A). The patient showed lower POLG and SSBP1 expression than his healthy brothers and the general population of a similar age. Notably, c.868C in the wild-type allele was highly methylated in the patient compared to the same site in both his healthy brothers. These results suggest that the co- deficient expression of POLG and SSBP1 genes could contribute to the development of mtDNA deletion.

SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance

“…Two of these variants, namely c.113G>A p.(Arg38Gln) and c.320G>A p.(Arg107Gln), have been previously reported in multiple families. 6 – 9 …”

“… 5 , 21 , 22 MtSSB (SSBP1, encoded by SSBP1 ) is an indispensable component of the mtDNA replication machinery and, as demonstrated previously, defects in SSBP1 may lead to an isolated or syndromic phenotype characterized by optic atrophy and retinal dystrophy. 1 , 6 – 9 …”

“…Recently, missense variants in SSBP1 have been reported to cause autosomal dominant mitochondrial optic atrophy and retinal dystrophy with or without mitochondrial depletion. 1 , 6 – 9 To date, 16 families (79 affected individual) are reported in the literature with optic atrophy as an unifying clinical feature observed in all affected individuals. Fifty-five percent of examined affected individuals (33/60) showed a variable degree of retinal dystrophy with the majority (23/33 [69.7%]) having a characteristic loss of the outer retina at the fovea.…”

Characterizing Organelles in Live Stem Cells Using Label-Free Optical Diffraction Tomography

“…hiPSCs were derived from peripheral blood mononuclear cells (PBMCs) and cultured in StemMACS supplemented with 100 U/ml penicillin and 100 U/ml streptomycin at 37°C in an atmosphere containing 5% CO 2 ( So et al, 2020 ). Fibroblasts were derived from human skin and cultured in DMEM/F-12 supplemented with 10% FBS, 100 U/ml penicillin, and 100 U/ml streptomycin at 37°C in an atmosphere containing 5% CO 2 ( Lee et al, 2021 ). For live cell microscopy, stem cells and fibroblasts were plated in Tomo‐dishes (Tomocube, Korea)…”

The 5′-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1)

“…Critical to the maintenance of mtDNA genome stability are the proteins involved in mtDNA replication. Many disease-associated mutations have been identified in genes encoding these proteins, such as the mtDNA polymerase γ (pol γ) complex ( POLGA and POLGB ) ( 7 , 8 ), the replicative helicase ( TWNK ) ( 9 ), DNA replication helicase/nuclease 2 ( DNA2 ) ( 10 ), mitochondrial genome maintenance exonuclease 1 ( MGME1 ) ( 11 ), and mitochondrial single-stranded DNA-binding protein ( SSBP1 ) ( 12 , 13 , 14 , 15 , 16 ).…”