DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
04 Jan 2024
04 Jan 2024
Historique:
received:
25
08
2023
accepted:
27
11
2023
revised:
31
10
2023
medline:
5
1
2024
pubmed:
5
1
2024
entrez:
4
1
2024
Statut:
aheadofprint
Résumé
DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.
Identifiants
pubmed: 38177406
doi: 10.1038/s41431-023-01516-4
pii: 10.1038/s41431-023-01516-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.
Références
Barresi R, Campbell KP. Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci. 2006;119:199–207.
doi: 10.1242/jcs.02814
pubmed: 16410545
Ervasti JM, Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol. 1993;122:809–23.
doi: 10.1083/jcb.122.4.809
pubmed: 8349731
Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S. Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell. 1994;77:675–86.
doi: 10.1016/0092-8674(94)90052-3
pubmed: 8205617
Henry MD, Campbell KP. Dystroglycan inside and out. Curr Opin Cell Biol. 1998;10:602–7.
Cohn RD, Henry MD, Michele DE, Barresi R, Saito F, Moore SA, et al. Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell. 2002;110:639–48.
doi: 10.1016/S0092-8674(02)00907-8
pubmed: 12230980
Jacobson C, Côté PD, Rossi SG, Rotundo RL, Carbonetto S. The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol. 2001;152:435–50.
doi: 10.1083/jcb.152.3.435
pubmed: 11157973
pmcid: 2195998
Hohenester E, Yurchenco PD. Laminins in basement membrane assembly. Cell Adh Migr. 2013;7:56–63.
doi: 10.4161/cam.21831
pubmed: 23076216
pmcid: 3544787
Durbeej M, Campbell KP. Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. Curr Opin Genet Dev. 2002;12:349–61.
doi: 10.1016/S0959-437X(02)00309-X
pubmed: 12076680
Barresi R, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz JS, et al. LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med. 2004;10:696–703.
doi: 10.1038/nm1059
pubmed: 15184894
Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature. 2002;418:422–5.
doi: 10.1038/nature00838
pubmed: 12140559
Kyriakides T, Angelini C, Vilchez J, Hilton-Jones D. European Federation of the Neurological Societies guidelines on the diagnostic approach to paucisymptomatic or asymptomatic hyperCKemia. Muscle Nerve. 2020;61:E14–E15.
doi: 10.1002/mus.26777
pubmed: 31820461
Fan L, Miura S, Shimojo T, Sugino H, Fujioka R, Shibata H. A novel 1-bp deletion variant in DAG1 in Japanese familial asymptomatic hyper-CK-emia. Hum Genome Var. 2022;9:4.
doi: 10.1038/s41439-022-00182-0
pubmed: 35082294
pmcid: 8791931
Frost AR, Böhm SV, Sewduth RN, Josifova D, Ogilvie CM, Izatt L, et al. Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities. Eur J Hum Genet. 2010;18:852–5.
doi: 10.1038/ejhg.2010.28
pubmed: 20234391
pmcid: 2987357
Scala M, Nishikawa M, Ito H, Tabata H, Khan T, Accogli A, et al. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes. Brain. 2002;145:3308–27.
doi: 10.1093/brain/awac106
Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130:2725–35.
doi: 10.1093/brain/awm212
pubmed: 17878207
Sparks S, Quijano-Ro, S, Harper A, et al. Congenital muscular dystrophy overview. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews® Seattle (WA): University of Washington, Seattle; 2015. https://doi.org/10.1016/j.ajpath.2015.08.010 .
Godfrey C, Foley AR, Clement E, Muntoni F. Dystroglycanopathies: coming into focus. Curr Pediatr Rep. 2013;1:166–75.
Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, Beltrán-Valero de Bernabé D, Gündeşli H, et al. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med. 2011;364:939–46.
doi: 10.1056/NEJMoa1006939
pubmed: 21388311
pmcid: 3071687
Song D, Dai Y, Chen X, Fu X, Chang X, Wang N, et al. Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients. Clin Genet. 2021;99:384–95.
doi: 10.1111/cge.13886
pubmed: 33200426
Geis T, Marquard K, Rödl T, Reihle C, Schirmer S, von Kalle T, et al. Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leukodystrophy. Neurogenetics. 2013;14:205–13.
doi: 10.1007/s10048-013-0374-9
pubmed: 24052401
Dong M, Noguchi S, Endo Y, Hayashi YK, Yoshida S, Nonaka I, et al. DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of α-dystroglycan. Neurology. 2015;84:273–9.
doi: 10.1212/WNL.0000000000001162
pubmed: 25503980
Kanagawa M. Dystroglycanopathy: from Elucidation of molecular and pathological mechanisms to development of treatment methods. Int J Mol Sci. 2021;22:13162.
doi: 10.3390/ijms222313162
pubmed: 34884967
pmcid: 8658603
Gemelli C, Traverso M, Trevisan L, Fabbri S, Scarsi E, Carlini B, et al. An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia. Muscle Nerve. 2022;65:96–104.
doi: 10.1002/mus.27448
pubmed: 34687219
Scala M, Bianchi A, Bisulli F, Coppola A, Elia M, Trivisano M, et al. Advances in genetic testing and optimization of clinical management in children and adults with epilepsy. Expert Rev Neurother. 2020;2:251–69.
doi: 10.1080/14737175.2020.1713101
Boycott KM, Hartley T, Biesecker LG, Gibbs RA, Innes AM, Riess O, et al. A diagnosis for all rare genetic diseases: the horizon and the next frontiers. Cell. 2019;177:32–37.
doi: 10.1016/j.cell.2019.02.040
pubmed: 30901545
Kaplan J. Genomics and medicine: hopes and challenges. Gene Ther. 2002;9:658–61.
doi: 10.1038/sj.gt.3301739
pubmed: 12032681
Muse ED, Chen SF, Torkamani A. Monogenic and polygenic models of coronary artery disease. Curr Cardiol Rep. 2021;23:107.
doi: 10.1007/s11886-021-01540-0
pubmed: 34196841
pmcid: 8317496
Yao Q, Gorevic P, Shen B, Gibson G. Genetically transitional disease: a new concept in genomic medicine. Trends Genet. 2023;39:98–108.
doi: 10.1016/j.tig.2022.11.002
pubmed: 36564319
Colaco S, Nadkarni A. Borderline HbA2 levels: dilemma in diagnosis of beta-thalassemia carriers. Mutat Res Rev Mutat Res. 2021;788:108387.
doi: 10.1016/j.mrrev.2021.108387
pubmed: 34893152
de Freitas Nakata KC, da Silva Pereira PP, Salgado Riveros B. Creatine kinase test diagnostic accuracy in neonatal screening for duchenne muscular dystrophy: a systematic review. Clin Biochem. 2021;98:1–9.
doi: 10.1016/j.clinbiochem.2021.09.010
pubmed: 34626608
Park S, Maloney B, Caggana M, Tavakoli NP. Creatine kinase-MM concentration in dried blood spots from newborns and implications for newborn screening for Duchenne muscular dystrophy. Muscle Nerve. 2022;65:652–8.
doi: 10.1002/mus.27533
pubmed: 35307847
pmcid: 9322420
Nicolau S, Milone M, Liewluck T. Guidelines for genetic testing of muscle and neuromuscular junction disorders. Muscle Nerve. 2021;64:255–69.
doi: 10.1002/mus.27337
pubmed: 34133031