| Literature DB >> 30318146 |
Andrew T N Tebbenkamp1, Luis Varela2, Jinmyung Choi1, Miguel I Paredes1, Alice M Giani1, Jae Eun Song2, Matija Sestan-Pesa2, Daniel Franjic1, André M M Sousa1, Zhong-Wu Liu2, Mingfeng Li1, Candace Bichsel1, Marco Koch2, Klara Szigeti-Buck2, Fuchen Liu1, Zhuo Li1, Yuka I Kawasawa3, Constantinos D Paspalas1, Yann S Mineur4, Paolo Prontera5, Giuseppe Merla6, Marina R Picciotto7, Amy F T Arnsten7, Tamas L Horvath8, Nenad Sestan9.
Abstract
Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.Entities:
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Year: 2018 PMID： 30318146 PMCID： PMC6459420 DOI： 10.1016/j.cell.2018.09.014
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582