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DNAJB6 Isoform Specific Knockdown: Therapeutic Potential for LGMDD1

Findlay, Andrew R. and Paing, May M. and Daw, Jil A. and Bengoechea, Rocio and Pittman, Sara K. and Li, Shan and Wang, Feng and Miller, Timothy M. and True, Heather L. and Chou, Tsui-Fen and Weihl, Conrad C. (2022) DNAJB6 Isoform Specific Knockdown: Therapeutic Potential for LGMDD1. . (Unpublished)

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Dominant missense mutations in DNAJB6, an HSP40 co-chaperone, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests only DNAJB6b is responsible for disease pathogenesis. Mechanistic data supports either a toxic gain of function, a dominant negative mechanism, or a combination of both. Knockdown treatment strategies involving both isoforms carry risk as DNAJB6 knockout is embryonic lethal. We therefore developed an isoform specific knockdown approach using morpholinos. Selective reduction of each isoform was achievedin-vitroin primary mouse myotubes and human myoblasts, as well asin-vivoin mouse skeletal muscle. To assess isoform specific knockdown in LGMDD1, we created primary myotube cultures from aknock-inLGMDD1 mouse model. Using mass spectrometry, we identified an LGMDD1 protein signature related to protein homeostasis and myofibril structure. Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature towards wild type levels. While additionalin-vivofunctional data is required, these findings suggest selective reduction of DNAJB6b may be a viable therapeutic target for LGMDD1.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Findlay, Andrew R.0000-0002-8728-9833
Daw, Jil A.0000-0002-8002-076X
Bengoechea, Rocio0000-0002-9029-019X
Li, Shan0000-0002-0829-1821
Wang, Feng0000-0003-4742-2668
Miller, Timothy M.0000-0002-3424-5511
True, Heather L.0000-0003-4824-9529
Chou, Tsui-Fen0000-0003-2410-2186
Weihl, Conrad C.0000-0002-3816-6124
Alternate Title:DNAJB6 Isoform Knockdown in LGMDD1
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This work was supported by grants from: The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): ARF (K08AR075894, R03AR081395), CCW (R01AR068797, K24AR073317); The American Society of Gene and Cell therapy (ASGCT): ARF (Career Development Award); The Children’s Discovery Institute of Saint Louis Children’s Hospital: ARF (Faculty Scholar Award- MIFR20221004); and the LGMD-1D DNAJB6 Foundation and International Registry (ARF). Author Contributions: ARF: Conceptualization, formal analysis, funding acquisition, investigation, methodology, resources, supervision, validation, visualization, writing original draft, writing – review and editing. MMP, JAD, RB, SKP, SL, FW, TC: Investigation, methodology. HLT, TMM: Conceptualization, writing – review and editing. CCW: Conceptualization, funding acquisition, resources, supervision, validation, writing – review and editing. Competing Interest Statement. ARF and CCW are co-inventors on a pending patent application related to this publication (USPTO serial no. 17/932,996).
Funding AgencyGrant Number
American Society of Gene and Cell TherapyUNSPECIFIED
Saint Louis Children’s HospitalMIFR20221004
Record Number:CaltechAUTHORS:20230316-182861000.70
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:120177
Deposited By: George Porter
Deposited On:17 Mar 2023 23:16
Last Modified:17 Mar 2023 23:16

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