Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel atypical phenotypes.
LMNA
Myofibrillar myopathies
Protein aggregate myopathies
RYR1
TTN
Whole-exome sequencing
Journal
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
ISSN: 1590-3478
Titre abrégé: Neurol Sci
Pays: Italy
ID NLM: 100959175
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
04
05
2020
accepted:
01
11
2020
pubmed:
11
11
2020
medline:
10
7
2021
entrez:
10
11
2020
Statut:
ppublish
Résumé
Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype. We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM. In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement. Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.
Sections du résumé
BACKGROUND
BACKGROUND
Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype.
METHODS
METHODS
We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM.
RESULTS
RESULTS
In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement.
CONCLUSIONS
CONCLUSIONS
Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.
Identifiants
pubmed: 33170376
doi: 10.1007/s10072-020-04876-7
pii: 10.1007/s10072-020-04876-7
pmc: PMC7654353
doi:
Substances chimiques
Protein Aggregates
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2819-2827Subventions
Organisme : UE
ID : FP7-REGPOT-2012-CT2012-316254-BASTION
Références
Selcen D, Engel AG (2011) Myofibrillar myopathies. Handb Clin Neurol 101:143–154
doi: 10.1016/B978-0-08-045031-5.00011-6
Schröder R, Schoser B (2009) Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol 19:483–492
doi: 10.1111/j.1750-3639.2009.00289.x
Ferrer I, Olivé M (2008) Molecular pathology of myofibrillar myopathies. Expert Rev Mol Med 10:e25
doi: 10.1017/S1462399408000793
Vattemi G, Neri M, Piffer S, Vicart P, Gualandi F, Marini M, Guglielmi V, Filosto M, Tonin P, Ferlini A, Tomelleri G (2011) Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy. Acta Myol 30:121–126
pubmed: 22106715
pmcid: 3235861
Fichna JP, Maruszak A, Żekanowski C (2018) Myofibrillar myopathy in the genomic context. J Appl Genet 59:431–439
doi: 10.1007/s13353-018-0463-4
Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120
doi: 10.1093/bioinformatics/btu170
Li H, Durbin R (2009) Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics 25:1754–1760
doi: 10.1093/bioinformatics/btp324
Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A et al (2013) From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinformatics 43:11.10.1–11.1033
doi: 10.1002/0471250953.bi1110s43
Garrison E, Marth G (2012) Haplotype-based variant detection from short-read sequencing. arXiv preprint arXiv:1207.3907 [q-bio.GN]
Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle (URL: http://evs.gs.washington.edu/EVS/ ). Accessed May 2019
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291
doi: 10.1038/nature19057
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315
doi: 10.1038/ng.2892
Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7:Unit7.20
pubmed: 23315928
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
doi: 10.1038/nprot.2009.86
Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GL, Edwards KJ et al (2013) Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat 34:57–65
doi: 10.1002/humu.22225
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362
doi: 10.1038/nmeth.2890
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Jang W, Karapetyan K, Katz K, Liu C, Maddipatla Z, Malheiro A, McDaniel K, Ovetsky M, Riley G, Zhou G, Holmes JB, Kattman BL, Maglott DR (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067
doi: 10.1093/nar/gkx1153
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978–1980
doi: 10.1093/bioinformatics/bty897
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424
doi: 10.1038/gim.2015.30
Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L, Familial Dilated Cardiomyopathy Registry Research Group (2003) Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 41:771–780
doi: 10.1016/S0735-1097(02)02954-6
Cowan J, Li D, Gonzalez-Quintana J, Morales A, Hershberger RE (2010) Morphological analysis of 13 LMNA variants identified in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Circ Cardiovasc Genet 3:6–14
doi: 10.1161/CIRCGENETICS.109.905422
Petillo R, D'Ambrosio P, Torella A, Taglia A, Picillo E, Testori A, Ergoli M, Nigro G, Piluso G, Nigro V, Politano L (2015) Novel mutations in LMNA A/C gene and associated phenotypes. Acta Myol 34:116–119
pubmed: 27199538
pmcid: 4859074
Pfeffer G, Barresi R, Wilson IJ, Hardy SA, Griffin H, Hudson J, Elliott HR, Ramesh AV, Radunovic A, Winer JB, Vaidya S, Raman A, Busby M, Farrugia ME, Ming A, Everett C, Emsley HCA, Horvath R, Straub V, Bushby K, Lochmuller H, Chinnery PF, Sarkozy A (2014) Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry 85:331–338
doi: 10.1136/jnnp-2012-304728
Ohlsson M, Hedberg C, Brådvik B, Lindberg C, Tajsharghi H, Danielsson O, Melberg A, Udd B, Martinsson T, Oldfors A (2012) Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. Brain 135:1682–1694
doi: 10.1093/brain/aws103
Kang SM, Yoon MH, Park BJ (2018) Laminopathies; mutations on single gene and various human genetic diseases. BMB Rep 51:327–337
doi: 10.5483/BMBRep.2018.51.7.113
Maggi L, Carboni N, Bernasconi P (2016) Skeletal muscle laminopathies: a review of clinical and molecular features. Cells 5:33. https://doi.org/10.3390/cells5030033
doi: 10.3390/cells5030033
pmcid: 5040975
Dhawan PS, Liewluck T, Knapik J, Milone M (2018) Myofibrillar myopathy due to dominant LMNA mutations: a report of 2 cases. Muscle Nerve 57:E124–E126
doi: 10.1002/mus.26036
D'Amico A, Benedetti S, Petrini S, Sambuughin N, Boldrini R, Menditto I, Ferrari M, Verardo M, Goldfarb L, Bertini E (2005) Major myofibrillar changes in early onset myopathy due to de novo heterozygous missense mutation in lamin A/C gene. Neuromuscul Disord 15:847–850
doi: 10.1016/j.nmd.2005.09.007
Gommans IM, Vlak MH, de Haan A, van Engelen BG (2002) Calcium regulation and muscle disease. J Muscle Res Cell Motil 23:59–63
doi: 10.1023/A:1019984714528
Lawal TA, Todd JJ, Meilleur KG (2018) Ryanodine receptor 1-related myopathies: diagnostic and therapeutic approaches. Neurotherapeutics 15:885–899
doi: 10.1007/s13311-018-00677-1
Jungbluth H, Dowling JJ, Ferreiro A, Muntoni F (2016) RYR1 Myopathy Consortium. 217th ENMC International Workshop: RYR1-related myopathies, Naarden, the Netherlands, 29-31 January 2016. Neuromuscul Disord 26:624–633
doi: 10.1016/j.nmd.2016.06.001
Gu M, Zhang S, Hu J, Yuan Y, Wang Z, Da Y et al (2014) Novel RYR1 missense mutations in six Chinese patients with central core disease. Neurosci Lett 566:32–35
doi: 10.1016/j.neulet.2014.02.015
Kraeva N, Riazi S, Loke J, Frodis W, Crossan ML, Nolan K, Kraev A, MacLennan DH (2011) Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population. Can J Anaesth 58(6):504–513
doi: 10.1007/s12630-011-9494-6
Witting N, Werlauff U, Duno M, Vissing J (2017) Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. Neurol Genet 3(2):e140
doi: 10.1212/NXG.0000000000000140
Todd JJ, Sagar V, Lawal TA, Allen C, Razaqyar MS, Shelton MS, Chrismer IC, Zhang X, Cosgrove MM, Kuo A, Vasavada R, Jain MS, Waite M, Rajapakse D, Witherspoon JW, Wistow G, Meilleur KG (2018) Correlation of phenotype with genotype and protein structure in RYR1-related disorders. J Neurol 265(11):2506–2524
doi: 10.1007/s00415-018-9033-2
Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P (2016) Increasing role of titin mutations in neuromuscular disorders. J Neuromuscul Dis 3:293–308
doi: 10.3233/JND-160158
Palmio J, Evilä A, Chapon F, Tasca G, Xiang F, Brådvik B et al (2014) Hereditary myopathy with early respiratory failure: occurrence in various populations. J Neurol Neurosurg Psychiatry 85:345–353
doi: 10.1136/jnnp-2013-304965
Uruha A, Hayashi YK, Oya Y, Mori-Yoshimura M, Kanai M, Murata M, Kawamura M, Ogata K, Matsumura T, Suzuki S, Takahashi Y, Kondo T, Kawarabayashi T, Ishii Y, Kokubun N, Yokoi S, Yasuda R, Kira JI, Mitsuhashi S, Noguchi S, Nonaka I, Nishino I (2015) Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry 86:483–489
doi: 10.1136/jnnp-2014-309009
Yue D, Gao M, Zhu W, Luo S, Xi J, Wang B, Li Y, Cai S, Li J, Wang Y, Lu J, Zhao C (2015) New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure. Neuromuscul Disord 25:172–176
doi: 10.1016/j.nmd.2014.11.005
Toro C, Olivé M, Dalakas MC, Sivakumar K, Bilbao JM, Tyndel F, Vidal N, Farrero E, Sambuughin N, Goldfarb LG (2013) Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. BMC Neurol 13:29
doi: 10.1186/1471-2377-13-29
Pfeffer G, Elliott HR, Griffin H, Barresi R, Miller J, Marsh J, Evilä A, Vihola A, Hackman P, Straub V, Dick DJ, Horvath R, Santibanez-Koref M, Udd B, Chinnery PF (2012) Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain 135:1695–1713
doi: 10.1093/brain/aws102
Tasca G, Udd B (2018) Hereditary myopathy with early respiratory failure (HMERF): still rare, but common enough. Neuromuscul Disord 28:268–276
doi: 10.1016/j.nmd.2017.12.002
Phillips PC (2008) Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9:855–867
doi: 10.1038/nrg2452