Last update 01 Nov 2024

DWORF

Last update 01 Nov 2024

Basic Info

Synonyms

Dwarf open reading frame, DWORF, Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator DWORF

+ [3]

Introduction

Enhances the activity of ATP2A1/SERCA1 ATPase in sarcoplasmic reticulum by displacing ATP2A1/SERCA1 inhibitors, thereby acting as a key regulator of skeletal muscle activity. Does not directly stimulate SERCA pump activity. Enhances sarcoplasmic reticulum Ca(2+) uptake and myocyte contractility by displacing the SERCA inhibitory peptides sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN).

Drugs associated with DWORF

AAV-delivered DWORF gene therapy (Tenaya Therapeutics)

Target

DWORF

Mechanism

DWORF modulators

Active Org.

Tenaya Therapeutics, Inc.

Originator Org.

Tenaya Therapeutics, Inc.

Active Indication

Cardiomyopathies [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

DWORF

Target

DWORF

Mechanism

DWORF modulators

Active Org.

Tenaya Therapeutics, Inc.

Originator Org.

Tenaya Therapeutics, Inc.

Active Indication

Cardiomyopathy, Dilated [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DWORF

100 Translational Medicine associated with DWORF

0 Patents (Medical) associated with DWORF

Literatures (Medical) associated with DWORF

01 Jul 2024·Cell Calcium

Phosphorylation of phospholamban promotes SERCA2a activation by dwarf open reading frame (DWORF)

Article

Author: Kahn, Daniel ; Zima, Aleksey V ; Karkut, Patryk ; Bovo, Elisa ; Robia, Seth L ; Jamrozik, Thomas

In cardiac myocytes, the type 2a sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) plays a key role in intracellular Ca regulation. Due to its critical role in heart function, SERCA2a activity is tightly regulated by different mechanisms, including micropeptides. While phospholamban (PLB) is a well-known SERCA2a inhibitor, dwarf open reading frame (DWORF) is a recently identified SERCA2a activator. Since PLB phosphorylation is the most recognized mechanism of SERCA2a activation during adrenergic stress, we studied whether PLB phosphorylation also affects SERCA2a regulation by DWORF. By using confocal Ca imaging in a HEK293 expressing cell system, we analyzed the effect of the co-expression of PLB and DWORF using a bicistronic construct on SERCA2a-mediated Ca uptake. Under these conditions of matched expression of PLB and DWORF, we found that SERCA2a inhibition by non-phosphorylated PLB prevails over DWORF activating effect. However, when PLB is phosphorylated at PKA and CaMKII sites, not only PLB's inhibitory effect was relieved, but SERCA2a was effectively activated by DWORF. Förster resonance energy transfer (FRET) analysis between SERCA2a and DWORF showed that DWORF has a higher relative affinity for SERCA2a when PLB is phosphorylated. Thus, SERCA2a regulation by DWORF responds to the PLB phosphorylation status, suggesting that DWORF might contribute to SERCA2a activation during conditions of adrenergic stress.

01 Mar 2024·American Journal of Physiology-Heart and Circulatory Physiology

Deletion of DWORF does not affect cardiac function in aging and in PLN-R14del cardiomyopathy

Article

Author: de Boer, Rudolf A ; Silljé, Herman H W ; Oliveira Nunes Teixeira, Vivian ; Zijlstra, Sietske N ; Stege, Nienke M ; Feringa, Anna M

Although DWORF overexpression significantly delayed heart failure development and strongly prolonged life span in PLN-R14del mice, the current study shows that deletion of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, DWORF appears to be dispensable for cardiac function during aging. Changes in DWORF gene expression are therefore unlikely to contribute to the clinical heterogeneity observed in patients with PLN-R14del cardiomyopathy.

08 Dec 2023·Circulation Research

DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters

Article

Author: Giepmans, Ben N.G. ; Olson, Eric N. ; Bassel-Duby, Rhonda ; van der Velden, Jolanda ; Silljé, Herman H.W. ; Makarewich, Catherine A. ; Wolters, Anouk H.G. ; Stege, Nienke M. ; Oliveira Nunes Teixeira, Vivian ; Feringa, Anna M. ; Kuster, Diederik W.D. ; de Boer, Rudolf A. ; Schouten, Elisabeth M. ; Eijgenraam, Tim R.

BACKGROUND: The p.Arg14del variant of the PLN (phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease. Dwarf open reading frame (DWORF) has been shown to counteract PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER). Here, we investigated the potential disease-modulating action of DWORF in this cardiomyopathy and its effects on calcium handling and PLN aggregation. METHODS: We studied a PLN-R14del mouse model, which develops cardiomyopathy with similar characteristics as human patients, and explored whether cardiac DWORF overexpression could delay cardiac deterioration. To this end, R14 Δ/Δ (homozygous PLN-R14del) mice carrying the DWORF transgene (R14 Δ/Δ DWORF Tg [R14 Δ/Δ mice carrying the DWORF transgene]) were used. RESULTS: DWORF expression was suppressed in hearts of R14 Δ/Δ mice with severe heart failure. Restoration of DWORF expression in R14 Δ/Δ mice delayed cardiac fibrosis and heart failure and increased life span >2-fold (from 8 to 18 weeks). DWORF accelerated sarcoplasmic reticulum calcium reuptake and relaxation in isolated cardiomyocytes with wild-type PLN, but in R14 Δ/Δ cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14 Δ/Δ and R14 Δ/Δ DWORF Tg . Rather, DWORF overexpression delayed the appearance and formation of large pathogenic perinuclear PLN clusters. Careful examination revealed colocalization of sarcoplasmic reticulum markers with these PLN clusters in both R14 Δ/Δ mice and human p.Arg14del PLN heart tissue, and hence these previously termed aggregates are comprised of abnormal organized S/ER. This abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiomyocyte cell loss and replacement fibrosis, consequently resulting in cardiac dysfunction. CONCLUSIONS: Disorganized S/ER is a major characteristic of PLN-R14del cardiomyopathy in humans and mice and results in cardiomyocyte death. DWORF overexpression delayed PLN-R14del cardiomyopathy progression and extended life span in R14 Δ/Δ mice, by reducing abnormal S/ER clusters.

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DWORF

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