Whole sequence of the mitochondrial DNA genome of Kearns Sayre Syndrome patients: Identification of deletions and variants

Abstract

Whole sequence of the mitochondrial DNA genome of Kearns Sayre Syndrome patients: identification of deletions and variants Mitochondria both produce the energy of the cell as ATP via respiration and regulate cellular metabolism. Accordingly, any deletion or mutation in the mitochondrial DNA (mtDNA) may result in a disease. One of these diseases is Kearns Sayre syndrome (KSS), described for the first time in 1958, where different large-scale deletions of different sizes and at different positions have been reported in the mitochondrial genome of patients with similar clinical symptoms. In this study, sequences of the mitochondrial genome of three patients with clinic features of KSS were analyzed. Our results revealed the position, heteroplasmy percentage, size of deletions, and their haplogroups. Two patients contained deletions reported previously and one patient showed a new deletion not reported previously. These results display for the first time a systematic analysis of mtDNA variants in the whole mtDNA genome of patients with KSS to help to understand their association with the disease.

Mitochondrial DNA Integrity: Role in Health and Disease

“…Using databases of mtDNA sequence and variation such as the comprehensive MITOMAP initiative [172], a number of associations between specific mitochondrial mutations and proclivity or protection from disease have been reported. For instance, mtDNA mutations and deletions are implicated in many severe diseases (Table 2), including Mitochondrial Encephalopathy, Lactic acidosis, and Stroke-like episodes (MELAS), Kearns-Sayre Syndrome (KSS), Pearson syndrome, and in about 20% of cases of Leigh syndrome [173,174,175,176]. Like many severe maladies of mitochondrial origin, MELAS is typically an early-onset disease, with most patients developing symptoms before age twenty.…”

“…MELAS is characterized by seizures, headaches, and stroke [173]. KSS is another early-onset neuromuscular disease characterized by pigmentary retinopathy and cardiac conduction defects, among other symptoms [176]. Pearson syndrome is often fatal in infancy and is characterized by exocrine pancreas insufficiency and sideroblastic anemia [174].…”

Differential diagnosis of POLG related disorders: What to keep in mind when multiorgan system is involved?

“…Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness, is relatively benign [53]. g) BCS1L-related disorders: Pathogenic variants in BCS1L are associated with GRACILE (growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) syndrome, Bjørnstad syndrome (congenital profound hearing loss and pili torti), and an overlapping GRACILE syndrome-Bjørnstad syndrome phenotype.…”

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

“…Since KSS was first reported by Kearns and Sayre (1958), there have been many reports describing deletions of different sizes and at different mtDNA positions among patients (Holt et al, 1988;Nelson et al, 1989;Montiel-Sosa et al, 2013;Damas et al, 2014;Saldaña-Martínez et al, 2019). The most common pathogenic large-scale deletion of 4977 bp (the so-called`common deletion') is precisely flanked by perfect direct repeats (DR) of 13 bp, at nucleotide positions 13,447-13,459 (within the ND5 gene) at the 5' end, and at positions 8470-8482 (within the ATPase8 gene) at the 3' end (Schon et al, 1989;Samuels et al, 2004).…”