Project description:Analysis of genes and pathways related to psychomotor retardation symptoms in patients with major depressive disorder. Results indicate that psychomotor slowing is associated with enrichment of inflammatory and metabolic pathways in unmedicated patients with depression.
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.