Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report.
CAPN3
Compound heterozygosity
LGMDR1
Splicing variant
cDNA assay
Journal
BMC musculoskeletal disorders
ISSN: 1471-2474
Titre abrégé: BMC Musculoskelet Disord
Pays: England
ID NLM: 100968565
Informations de publication
Date de publication:
04 Dec 2021
04 Dec 2021
Historique:
received:
07
05
2021
accepted:
28
11
2021
entrez:
5
12
2021
pubmed:
6
12
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband's cDNA sample. The results revealed that this splicing variant disrupts the original 3' splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.
Sections du résumé
BACKGROUND
BACKGROUND
Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis.
CASE PRESENTATION
METHODS
In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband's cDNA sample. The results revealed that this splicing variant disrupts the original 3' splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)).
CONCLUSIONS
CONCLUSIONS
Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.
Identifiants
pubmed: 34863162
doi: 10.1186/s12891-021-04920-3
pii: 10.1186/s12891-021-04920-3
pmc: PMC8645139
doi:
Substances chimiques
Muscle Proteins
0
CAPN3 protein, human
EC 3.4.22.-
Calpain
EC 3.4.22.-
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1020Informations de copyright
© 2021. The Author(s).
Références
J Med Genet. 2005 Sep;42(9):686-93
pubmed: 16141003
Neuromuscul Disord. 2007 Feb;17(2):143-7
pubmed: 17157502
Hum Mutat. 2011 May;32(5):557-63
pubmed: 21520333
Nucleic Acids Res. 2001 Jan 1;29(1):308-11
pubmed: 11125122
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Tanaffos. 2014;13(4):41-7
pubmed: 25852760
Neurogenetics. 2008 Jul;9(3):173-82
pubmed: 18563459
BMC Bioinformatics. 2012 Jun 18;13:134
pubmed: 22708584
Front Neurosci. 2021 Oct 14;15:692482
pubmed: 34720847
Nat Methods. 2014 Apr;11(4):361-2
pubmed: 24681721
Hum Mutat. 2003 Jun;21(6):577-81
pubmed: 12754702
J Biol Chem. 2018 Mar 16;293(11):4056-4070
pubmed: 29382717
Eur J Hum Genet. 2009 May;17(5):598-603
pubmed: 18854869
Exp Anim. 2010;59(5):549-66
pubmed: 21030783
Sci Rep. 2016 Jun 22;6:28400
pubmed: 27329541
Genes (Basel). 2019 Jun 10;10(6):
pubmed: 31185693
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
Nature. 2010 Oct 28;467(7319):1061-73
pubmed: 20981092
Hum Genet. 1992 Sep-Oct;90(1-2):41-54
pubmed: 1427786
Hum Mutat. 2010 Sep;31(9):E1658-69
pubmed: 20635405
Biochem Soc Trans. 2018 Jun 19;46(3):503-512
pubmed: 29626148
Neuromuscul Disord. 2018 Aug;28(8):702-710
pubmed: 30055862
Hum Mutat. 1998;Suppl 1:S298-300
pubmed: 9452114
Genome Biol. 2019 Nov 28;20(1):254
pubmed: 31779641
Nucleic Acids Res. 2002 Jan 1;30(1):38-41
pubmed: 11752248
Int J Mol Sci. 2019 Sep 13;20(18):
pubmed: 31540302
Genes Cells. 2014 Nov;19(11):830-41
pubmed: 25252031
Nucleic Acids Res. 2016 Feb 29;44(4):1483-95
pubmed: 26773057
Neurology. 2014 Oct 14;83(16):1453-63
pubmed: 25313375
J Med Genet. 2007 Oct;44(10):609-14
pubmed: 17526799
Nucleic Acids Res. 2012 Aug;40(15):e115
pubmed: 22730293
J Hum Genet. 2017 Feb;62(2):243-252
pubmed: 27708273
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515
pubmed: 30395287
Hum Genet. 2017 Sep;136(9):1279-1289
pubmed: 28391525
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Hum Mutat. 2007 Feb;28(2):150-8
pubmed: 17001642
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
pubmed: 15608251
Nucleic Acids Res. 2014 Jan;42(Database issue):D222-30
pubmed: 24288371
BMC Genomics. 2002 May 24;3:13
pubmed: 12057013
Nat Rev Genet. 2007 Oct;8(10):749-61
pubmed: 17726481
Nucleic Acids Res. 2009 May;37(9):e67
pubmed: 19339519
Biochimie. 2016 Mar;122:169-87
pubmed: 26363099
J Clin Neurosci. 2018 Jul;53:229-231
pubmed: 29685414
F1000Res. 2014 Nov 18;3:282
pubmed: 25717368
Hum Mutat. 2012 May;33(5):803-8
pubmed: 22422702
Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5
pubmed: 24234437
Clin Genet. 2007 Dec;72(6):582-92
pubmed: 17979987
BMC Neurol. 2014 Aug 19;14:154
pubmed: 25135358