The Complex Landscape of DMD Mutations: Moving Towards Personalized Medicine

Overview

Journal Front Genet

Date 2024 Apr 10

PMID 38596212

Authors

Francesca Gatto

Silvia Benemei

Giulio Piluso

Luca Bello

Affiliations

Soon will be listed here.

Abstract

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.

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References

Ebrahimzadeh-Vesal R, Teymoori A, Azimi-Nezhad M, Hosseini F . Next Generation Sequencing approach to molecular diagnosis of Duchenne muscular dystrophy; identification of a novel mutation. Gene. 2017; 644:1-3. DOI: 10.1016/j.gene.2017.12.009. View

Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen G . Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009; 30(3):293-9. DOI: 10.1002/humu.20918. View

Andrews J, Lamb M, Conway K, Street N, Westfield C, Ciafaloni E . Differentiation of Pediatric-Onset Duchenne and Becker Muscular Dystrophy Subphenotypes Using Data from the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet). J Neuromuscul Dis. 2021; 9(1):171-178. PMC: 9059491. DOI: 10.3233/JND-210739. View

Bello L, Pegoraro E . The "Usual Suspects": Genes for Inflammation, Fibrosis, Regeneration, and Muscle Strength Modify Duchenne Muscular Dystrophy. J Clin Med. 2019; 8(5). PMC: 6571893. DOI: 10.3390/jcm8050649. View

Yao S, Chen Z, Yu Y, Zhang N, Jiang H, Zhang G . Current Pharmacological Strategies for Duchenne Muscular Dystrophy. Front Cell Dev Biol. 2021; 9:689533. PMC: 8417245. DOI: 10.3389/fcell.2021.689533. View

Broomfield J, Hill M, Guglieri M, Crowther M, Abrams K . Life Expectancy in Duchenne Muscular Dystrophy: Reproduced Individual Patient Data Meta-analysis. Neurology. 2021; 97(23):e2304-e2314. PMC: 8665435. DOI: 10.1212/WNL.0000000000012910. View

Birnkrant D, Bushby K, Bann C, Apkon S, Blackwell A, Brumbaugh D . Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018; 17(3):251-267. PMC: 5869704. DOI: 10.1016/S1474-4422(18)30024-3. View

van den Bergen J, Hiller M, Bohringer S, Vijfhuizen L, Ginjaar H, Chaouch A . Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants. J Neurol Neurosurg Psychiatry. 2014; 86(10):1060-5. PMC: 4602257. DOI: 10.1136/jnnp-2014-308409. View

Vetrone S, Montecino-Rodriguez E, Kudryashova E, Kramerova I, Hoffman E, Liu S . Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta. J Clin Invest. 2009; 119(6):1583-94. PMC: 2689112. DOI: 10.1172/JCI37662. View

10.

Zambon A, Waldrop M, Alles R, Weiss R, Conroy S, Moore-Clingenpeel M . Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications. Neurology. 2021; 98(7):e730-e738. PMC: 8865888. DOI: 10.1212/WNL.0000000000013246. View

11.

Vianello S, Pantic B, Fusto A, Bello L, Galletta E, Borgia D . SPP1 genotype and glucocorticoid treatment modify osteopontin expression in Duchenne muscular dystrophy cells. Hum Mol Genet. 2017; 26(17):3342-3351. DOI: 10.1093/hmg/ddx218. View

12.

Gazzoli I, Pulyakhina I, Verwey N, Ariyurek Y, Laros J, t Hoen P . Non-sequential and multi-step splicing of the dystrophin transcript. RNA Biol. 2015; 13(3):290-305. PMC: 4829307. DOI: 10.1080/15476286.2015.1125074. View

13.

Gualandi F, Rimessi P, Trabanelli C, Spitali P, Neri M, Patarnello T . Intronic breakpoint definition and transcription analysis in DMD/BMD patients with deletion/duplication at the 5' mutation hot spot of the dystrophin gene. Gene. 2006; 370:26-33. DOI: 10.1016/j.gene.2005.11.002. View

14.

Pegoraro E, Hoffman E, Piva L, Gavassini B, Cagnin S, Ermani M . SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology. 2010; 76(3):219-26. PMC: 3034396. DOI: 10.1212/WNL.0b013e318207afeb. View

15.

Crudele J, Chamberlain J . Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun. 2018; 9(1):3497. PMC: 6115392. DOI: 10.1038/s41467-018-05843-9. View

16.

Bladen C, Salgado D, Monges S, Foncuberta M, Kekou K, Kosma K . The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 2015; 36(4):395-402. PMC: 4405042. DOI: 10.1002/humu.22758. View

17.

Weiss R, Vieland V, Dunn D, Kaminoh Y, Flanigan K . Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy. Ann Neurol. 2018; 84(2):234-245. PMC: 6168392. DOI: 10.1002/ana.25283. View

18.

Neri M, Rossi R, Trabanelli C, Mauro A, Selvatici R, Falzarano M . The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study. Front Genet. 2020; 11:131. PMC: 7063120. DOI: 10.3389/fgene.2020.00131. View

19.

Keegan N . Pseudoexons of the DMD Gene. J Neuromuscul Dis. 2020; 7(2):77-95. PMC: 7175933. DOI: 10.3233/JND-190431. View

20.

Rimessi P, Fabris M, Bovolenta M, Bassi E, Falzarano S, Gualandi F . Antisense modulation of both exonic and intronic splicing motifs induces skipping of a DMD pseudo-exon responsible for x-linked dilated cardiomyopathy. Hum Gene Ther. 2010; 21(9):1137-46. DOI: 10.1089/hum.2010.010. View