Dataset Information

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

ABSTRACT:

Background

Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes.

Methods and results

We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model.

Conclusions

We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

SUBMITTER: Bello L

PROVIDER: S-EPMC10977446 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Bello Luca L Sabbatini Daniele D Fusto Aurora A Gorgoglione Domenico D Borin Giovanni Umberto GU Penzo Martina M Riguzzi Pietro P Villa Matteo M Vianello Sara S Calore Chiara C Melacini Paola P Vio Riccardo R Barp Andrea A D'Angelo Grazia G Gandossini Sandra S Politano Luisa L Berardinelli Angela A Messina Sonia S Vita Gian Luca GL Pedemonte Marina M Bruno Claudio C Albamonte Emilio E Sansone Valeria V Baranello Giovanni G Masson Riccardo R Astrea Guja G D'Amico Adele A Bertini Enrico E Pane Marika M Lucibello Simona S Mercuri Eugenio E Spurney Christopher C Clemens Paula P Morgenroth Lauren L Gordish-Dressman Heather H McDonald Craig M CM Hoffman Eric P EP Pegoraro Elena E

Journal of neuromuscular diseases 20240101 2

<h4>Background</h4>Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes.<h4>Methods and results</h4>We retrospectively collected 3138 echocardiogr ...[more]

PMID: 38363615

Similar Datasets

Project description:BackgroundWe are developing a novel therapy for Duchenne muscular dystrophy (DMD), involving the transplantation of autologous, skeletal muscle-derived stem cells that have been genetically corrected to express dystrophin. Dystrophin is normally expressed in activated satellite cells and in differentiated muscle fibres. However, in past preclinical validation studies, dystrophin transgenes have generally been driven by constitutive promoters that would be active at every stage of the myogenic differentiation process, including in proliferating muscle stem cells. It is not known whether artificial dystrophin expression would affect the properties of these cells.AimsOur aims are to determine if mini-dystrophin expression affects the proliferation or myogenic differentiation of DMD skeletal muscle-derived cells.MethodsSkeletal muscle-derived cells from a DMD patient were transduced with lentivirus coding for mini-dystrophins (R3-R13 spectrin-like repeats (ΔR3R13) or hinge2 to spectrin-like repeats R23 (ΔH2R23)) with EGFP (enhanced green fluorescence protein) fused to the C-terminus, driven by a constitutive promoter, spleen focus-forming virus (SFFV). Transduced cells were purified on the basis of GFP expression. Their proliferation and myogenic differentiation were quantified by ethynyl deoxyuridine (EdU) incorporation and fusion index. Furthermore, dystrophin small interfering ribonucleic acids (siRNAs) were transfected to the cells to reverse the effects of the mini-dystrophin. Finally, a phospho-mitogen-activated protein kinase (MAPK) array assay was performed to investigate signalling pathway changes caused by dystrophin expression.ResultsCell proliferation was not affected in cells transduced with ΔR3R13, but was significantly increased in cells transduced with ΔH2R23. The fusion index of myotubes derived from both ΔR3R13- and ΔH2R23 -expressing cells was significantly compromised in comparison to myotubes derived from non-transduced cells. Dystrophin siRNA transfection restored the differentiation of ΔH2R23-expressing cells. The Erk1/2- signalling pathway is altered in cells transduced with mini-dystrophin constructs.ConclusionsEctopic expression of dystrophin in cultured human skeletal muscle-derived cells may affect their proliferation and differentiation capacity. Caution should be taken when considering genetic correction of autologous stem cells to express dystrophin driven by a constitutive promoter.

Dataset Information

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background

Methods and results

Conclusions

Publications

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Similar Datasets

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