Project description:The dataset includes exome sequencing results for a patient with SSBP1 mutations that cause a complex optic atrophy spectrum disorder
Project description:The genetic defects leading to optic atrophy range from mitochondrial DNA (mtDNA) point mutations in Leber’s hereditary optic neuropathy (LHON), to dominant and recessive mutations affecting a cluster of nuclear genes implicated in mitochondrial dynamics. We performed WES in patients with an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions, to identify the genetic causes of this syndrome.
Project description:The nuclear receptor Nr2f1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, its mutations cause the Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including optic nerve atrophy, intellectual disability, and autistic traits. In this study, by genome-wide and in silico analyses we identified a wide set of nuclear-encoded mitochondrial genes as potential genomic targets under direct Nr2f1 transcriptional control in neurons. By combining mouse genetics, neuroanatomical and imaging approaches we demonstrated that conditional Nr2f1 loss-of-function within the adult mouse hippocampal neurogenic niche results in a reduced mitochondrial mass associated with mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, whose functional integration and survival are impaired. Importantly, we also found dysregulation of several mitochondrial genes and downregulation in levels of key mitochondrial proteins in the brain of mice heterozygous for Nr2f1, a validated BBSOAS model. Our data point to an active role of Nr2f1 in the mitochondrial gene expression regulatory network in neurons and support the involvement of mitochondrial dysfunction in BBSOAS pathogenesis.
Project description:MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation, and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM mediated supercomplex modulation and ISC biogenesis and suggest new pathways for therapeutics.
Project description:Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause Pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial Complex I and PDHc deficiency. Whole exome sequencing uncovered a known EXOSC3-mutation p.(D132A) as the underlying cause. In patient fibroblasts, >50% of the EXOSC3 protein was trapped in the cytosol. mtDNA-copy numbers in muscle were reduced to 40%, but mutations in the mtDNA and nuclear mitochondrial genes were excluded. RNA-seq of patient muscle showed highly increased mRNA-copy numbers, especially for genes encoding structural subunits of OXPHOS-complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.
Project description:LHON is a paraLeber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood and there has been no effective treatment or cure for this disorder. We use scRNA-seq to study the retinal cell-specific deficiencies caused by LHON-linked ND6P25L mutation.
Project description:Mitochondria are critical for metabolic homeostasis of the liver, and thus, mitochondrial dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein that also plays a role in cristae shaping. Hence, the OPA1 gene disruption has been shown to cause mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we deleted OPA1 in fully developed mouse liver and examined its effect.
Project description:This study aims to confirm the pathogenic role of the AFG3L2 F175S mutation in dominant optic atrophy (DOA) and elucidate its molecular mechanisms disrupting mitochondrial morphology and function.
