关键词:
Bipolar Disorder
Mitochondria
Mitochondrial-Dysfunction
Genetics
Mood Disorder
摘要:
Background: Mitochondrial disease is a group of rare diseases with highly variable clinical presentation. Diagnosis mainly focuses on identifying one pathogenic variant in either the nuclear or mitochondrial DNA (mtDNA) as the primary cause of mitochondrial disease. However, this strategy does not explain why many individuals carrying the same variant present subtly or vastly different clinical phenotypes. Methods: Here, we present a family with two deceased offspring with clinical diagnoses of cytochrome c oxidase (COX) deficiency, an unaffected sister, a mother with bipolar disorder, diabetes and fibromyalgia, and a father with a family history of Kearns-Sayre syndrome. We incorporated nuclear and mitochondrial next-generation sequencing and deep mitochondrial phenotyping to understand the genetic and biological connection amongst these complex diseases. Results: Our results revealed: 1) a paternally inherited pathogenic variant (chr15:89864114 T>C, ***955Cys) in DNA polymerase gamma, catalytic subunit (POLG); 2) maternally inherited mtDNA haplogroup X2g. In combination, these variants may explain the: (1) decreased mtDNA copy number; (2) decreased mitochondrial complexes III, IV, V; (3) decreased adenosine triphosphate, malate, dihydroxyacetone phosphate; and (4) increased pyruvate and glycerol 3-phosphate in fibroblasts from patients with COX deficiency. Conclusions: Our results show that the combination of a nuclear-encoded POLG variant and mtDNA haplogroup X2g-associated variants were present in those with COX deficiency. However, those without the clinical diagnosis of COX deficiency do not have the combination of those variants, suggesting that that bi-genomic analyses and deep mitochondrial phenotyping can lead to a novel understanding of complex disease phenotypes within a family. Supported By: CIHRMOP13334 Keywords: Bipolar Disorder, Mitochondria, Mitochondrial-Dysfunction, Genetics, Mood Disorder