@article{8aa6f2bde92f4637aa3b5a706412f82c,
title = "The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development",
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. Reduced copy number of DNAJC30, now shown to interact with the mitochondrial ATP synthase, leads to mitochondrial dysfunction underlying neuronal defects in Williams syndrome.",
author = "Tebbenkamp, {Andrew T.N.} and Luis Varela and Jinmyung Choi and Paredes, {Miguel I.} and Giani, {Alice M.} and Song, {Jae Eun} and Matija Sestan-Pesa and Daniel Franjic and Sousa, {Andr{\'e} M.M.} and Liu, {Zhong Wu} and Mingfeng Li and Candace Bichsel and Marco Koch and Klara Szigeti-Buck and Fuchen Liu and Zhuo Li and Kawasawa, {Yuka I.} and Paspalas, {Constantinos D.} and Mineur, {Yann S.} and Paolo Prontera and Giuseppe Merla and Picciotto, {Marina R.} and Arnsten, {Amy F.T.} and Horvath, {Tamas L.} and Nenad Sestan",
note = "Funding Information: All experiments using animals were carried out in accordance with a protocol approved by Yale University{\textquoteright}s Committee on Animal Research and NIH guidelines. The Dnajc30 knockout mouse strains used for this research project were created from ES cell clones 16795A-A9 and 16795A-F1, obtained from the NCRR-NIH supported KOMP Repository ( www.komp.org ) and generated by Regeneron Pharmaceuticals, Inc. for the NIH funded Knockout Mouse Project (KOMP). Methods used to create the Velocigene targeted alleles have been published ( Valenzuela et al., 2003 ). The ES cells were used to create chimera at Yale Genome Editing Center, which were then backcrossed to make congenic C57BL/6N mice. Some heterozygous males were returned to KOMP as a part of their resubmission and sharing program. The Thy-1-YFP-H transgenic mice were obtained from the Jackson Laboratory. Funding Information: Human tissue was obtained from the University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of the NIH NeuroBioBank. We thank The Genomic and Genetic Disorders Biobank, a member of the Telethon Network of Genetic Biobanks funded by Telethon Italy (project no. GTB12001G) for the banking of biospecimens. We thank Angus Nairn, Arthur Horwich, and Sestan lab members for helpful discussions. This work was supported by the Brown-Coxe and 5T32NS007224-27 fellowships (A.T.N.T.); Telethon Foundation – Italy (Grant no. GGP14265); Italian Ministry of Health (Ricerca Corrente) (G.M.); DA037566 and MH076681 from the NIH (M.R.P.); NIH Pioneer Award DP1AG047744-01 (A.F.T.A.); AG052005, AG052986, AG051459, DK111178 from the NIH and NKFI-126998 from the Hungarian National Research, Development and Innovation Office (T.L.H.); and MH106934, MH106874, MH116488, MH110926 and MH109904 from the NIH (N.S.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "1",
doi = "10.1016/j.cell.2018.09.014",
language = "English (US)",
volume = "175",
pages = "1088--1104.e23",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}