@article {718,
	title = {Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.},
	journal = {J Clin Invest},
	volume = {129},
	year = {2019},
	month = {2019 Dec 02},
	pages = {5568-5583},
	abstract = {<p>Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.</p>},
	issn = {1558-8238},
	doi = {10.1172/JCI130600},
	author = {Morelli, Kathryn H and Griffin, Laurie B and Pyne, Nettie K and Wallace, Lindsay M and Fowler, Allison M and Oprescu, Stephanie N and Takase, Ryuichi and Wei, Na and Meyer-Schuman, Rebecca and Mellacheruvu, Dattatreya and Kitzman, Jacob O and Kocen, Samuel G and Hines, Timothy J and Spaulding, Emily L and Lupski, James R and Nesvizhskii, Alexey and Mancias, Pedro and Butler, Ian J and Yang, Xiang-Lei and Hou, Ya-Ming and Antonellis, Anthony and Harper, Scott Q and Burgess, Robert W}
}
@article {673,
	title = {Reanalysis of Clinical Exome Sequencing Data.},
	journal = {N Engl J Med},
	volume = {380},
	year = {2019},
	month = {2019 06 20},
	pages = {2478-2480},
	keywords = {Exome, Genetic Diseases, Inborn, Genetic Testing, Humans, Mutation, Phenotype, Sequence Analysis, DNA, Whole Exome Sequencing},
	issn = {1533-4406},
	doi = {10.1056/NEJMc1812033},
	author = {Liu, Pengfei and Meng, Linyan and Normand, Elizabeth A and Xia, Fan and Song, Xiaofei and Ghazi, Andrew and Rosenfeld, Jill and Magoulas, Pilar L and Braxton, Alicia and Ward, Patricia and Dai, Hongzheng and Yuan, Bo and Bi, Weimin and Xiao, Rui and Wang, Xia and Chiang, Theodore and Vetrini, Francesco and He, Weimin and Cheng, Hanyin and Dong, Jie and Gijavanekar, Charul and Benke, Paul J and Bernstein, Jonathan A and Eble, Tanya and Eroglu, Yasemen and Erwin, Deanna and Escobar, Luis and Gibson, James B and Gripp, Karen and Kleppe, Soledad and Koenig, Mary K and Lewis, Andrea M and Natowicz, Marvin and Mancias, Pedro and Minor, LaKeesha and Scaglia, Fernando and Schaaf, Christian P and Streff, Haley and Vernon, Hilary and Uhles, Crescenda L and Zackai, Elaine H and Wu, Nan and Sutton, V Reid and Beaudet, Arthur L and Muzny, Donna and Gibbs, Richard A and Posey, Jennifer E and Lalani, Seema and Shaw, Chad and Eng, Christine M and Lupski, James R and Yang, Yaping}
}
@article {135,
	title = {Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.},
	journal = {Cell Rep},
	volume = {12},
	year = {2015},
	month = {2015 Aug 18},
	pages = {1169-83},
	abstract = {<p>Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in \~{} 45\% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.</p>},
	keywords = {Animals, Charcot-Marie-Tooth Disease, Exome, Female, Genetic Load, Genetic Variation, HSP40 Heat-Shock Proteins, Humans, Male, Mutation, Myelin P2 Protein, Pedigree, Penetrance, Peripheral Nervous System Diseases, Phenotype, Serine C-Palmitoyltransferase, Suppression, Genetic, Zebrafish},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2015.07.023},
	author = {Gonzaga-Jauregui, Claudia and Harel, Tamar and Gambin, Tomasz and Kousi, Maria and Griffin, Laurie B and Francescatto, Ludmila and Ozes, Burcak and Karaca, Ender and Jhangiani, Shalini N and Bainbridge, Matthew N and Lawson, Kim S and Pehlivan, Davut and Okamoto, Yuji and Withers, Marjorie and Mancias, Pedro and Slavotinek, Anne and Reitnauer, Pamela J and Goksungur, Meryem T and Shy, Michael and Crawford, Thomas O and Koenig, Michel and Willer, Jason and Flores, Brittany N and Pediaditrakis, Igor and Us, Onder and Wiszniewski, Wojciech and Parman, Yesim and Antonellis, Anthony and Muzny, Donna M and Katsanis, Nicholas and Battaloglu, Esra and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R}
}
