Iranian
Biomedical Journal
Volume 28, Issue 5 And 6 (9-2024)
IBJ 2024, 28(5 And 6): 297-304 |
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Soltani N, Shahbazi Z, Karimipoor M, Fallah M S, Zafarghandi Motlagh F, Amini M, et al . Mutations in COL6A Gene Family Responsible for Muscular Dystrophies in Three Unrelated Families. IBJ 2024; 28 (5 and 6) :297-304
URL: http://ibj.pasteur.ac.ir/article-1-4018-en.html
URL: http://ibj.pasteur.ac.ir/article-1-4018-en.html
Nasibeh Soltani 
, Zahra Shahbazi , Morteza Karimipoor , Mohammad Sadegh Fallah , Fatemeh Zafarghandi Motlagh , Masoume Amini , Mojdeh Jamali , Hamideh Bagherian , Razie Zeinali , Sirous Zeinali *
, Zahra Shahbazi , Morteza Karimipoor , Mohammad Sadegh Fallah , Fatemeh Zafarghandi Motlagh , Masoume Amini , Mojdeh Jamali , Hamideh Bagherian , Razie Zeinali , Sirous Zeinali *
Abstract:
Background: Muscular dystrophy is an inherited disease with clinical and genetic heterogeneity. Muscle weakness is the primary symptom of these disorders that often leads to disability and death. The overall prevalence for all types of muscular dystrophies worldwide is 19.8-25.1 per 100.000 population. Autosomal recessive types of muscular dystrophies are more common in Iran, likely due to the high rate of consanguineous marriage. We aimed at deciphering molecular defects in three unrelated families with muscular dystrophies not related to Duchene muscular dystrophy (MD) or limb girdle muscular dystrophies. We are reporting families having affected children with MD owing to the mutations in three genes related to the COL6A (collagen type VI, alpha subunit) gene family.
Methods: Three unrelated families, who had at least one member affected with MD and for whom a definite molecular diagnosis was not provided by routine methods, were investigated by WES and confirmed by Sanger sequencing.
Results: In the first family, a homozygous variant was found in the COL6A3 gene (NM_004369.4:c.4390C>T:p.Arg1464Ter), which explains the clinical symptoms observed in this family. In the second family, two homozygote missense variants with possible relevance to the patient’s phenotype were identified in COL6A1 and COL6A2 genes (NM_001848.2:c.803A>G: p.Glu268Gly and NM_001849.3:c.2489G>A:p.Arg830Gln). Also, a heterozygous pathogenic variant in the COL6A2 gene (NM_001849.3: c.1053+1G>T) was detected in the third family.
Conclusion: WES can serve as an effective method for detecting the causative mutations in families with unresolved cases of MD. The data provided herein broadens the spectrum of mutations causing MD in Iran.
Methods: Three unrelated families, who had at least one member affected with MD and for whom a definite molecular diagnosis was not provided by routine methods, were investigated by WES and confirmed by Sanger sequencing.
Results: In the first family, a homozygous variant was found in the COL6A3 gene (NM_004369.4:c.4390C>T:p.Arg1464Ter), which explains the clinical symptoms observed in this family. In the second family, two homozygote missense variants with possible relevance to the patient’s phenotype were identified in COL6A1 and COL6A2 genes (NM_001848.2:c.803A>G: p.Glu268Gly and NM_001849.3:c.2489G>A:p.Arg830Gln). Also, a heterozygous pathogenic variant in the COL6A2 gene (NM_001849.3: c.1053+1G>T) was detected in the third family.
Conclusion: WES can serve as an effective method for detecting the causative mutations in families with unresolved cases of MD. The data provided herein broadens the spectrum of mutations causing MD in Iran.
Type of Study: Full Length/Original Article |
Subject:
Molecular Genetics & Genomics
References
1. Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687-95. [DOI:10.1016/S0140-6736(02)07815-7]
2. Brown SC, Muntoni F, Sewry CA. Non-sarcolemmal muscular dystrophies. Brain Pathol. 2001;11(2):193-205. [DOI:10.1111/j.1750-3639.2001.tb00392.x]
3. Nigro V, Piluso G. Spectrum of muscular dystrophies associated with sarcolemmal-protein genetic defects. Biochim Biophys Acta. 2015;1852(4):585-93. [DOI:10.1016/j.bbadis.2014.07.023]
4. Carter JC, Sheehan DW, Prochoroff A, Birnkrant DJ. Muscular Dystrophies. Clin Chest Med. 2018;39(2):377-89. [DOI:10.1016/j.ccm.2018.01.004]
5. Mercuri E, Muntoni F. Muscular dystrophies. Lancet. 2013;381(9869):845-60. [DOI:10.1016/S0140-6736(12)61897-2]
6. Theadom A, Rodrigues M, Roxburgh R, Balalla Sh, Higgins Ch, Bhattacharjee R, et al. Prevalence of muscular dystrophies: a Systematic literature review. Neuroepidemiology. 2014;43(3-4):259-68. [DOI:10.1159/000369343]
7. Rahimov F, Kunkel LM. Cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 2013;201(4):499-510. [DOI:10.1083/jcb.201212142]
8. Gaina G, Budisteanu M, Manole E, Lonica E. Clinical and Molecular Diagnosis in Muscular Dystrophies. Muscul Dystrophies. IntechOpen; 2019. Available from: http://dx.doi.org/10.5772/intechopen.85339 [DOI:10.5772/intechopen.85339]
9. Dardas Z, Swedan S, Al-Sheikh Qassem A, Azab B. The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families. Eur J Med Genet. 2020;63(4):103845. [DOI:10.1016/j.ejmg.2020.103845]
10. Rabbani B, Mahdieh N, Hosomichi K, Nakaoka H, Inoue I. Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders. J Hum Genet. 2012;57(10):621-32. [DOI:10.1038/jhg.2012.91]
11. Majewski J, Schwartzentruber J, Lalonde E, Montpetit A, Jabado N. What can exome sequencing do for you? J Med Genet. 2011;48(9):580-9. [DOI:10.1136/jmedgenet-2011-100223]
12. Gautam A. Isolation of DNA from Blood Samples by Salting Method. In: DNA and RNA Isolation Techniques for Non-Experts. Techniques in Life Science and Biomedicine for the Non-Expert. Springer, Cham.
https://doi.org/10.1007/978-3-030-94230-4_12 [DOI:10.1007/978-3-030-94230-4_12.]
13. Qamar W, Khan MR, Arafah A. Optimization of conditions to extract high quality DNA for PCR analysis from whole blood using SDS-proteinase K method. Saudi J Biol Sci. 2017;24(7):1465-9. [DOI:10.1016/j.sjbs.2016.09.016]
14. Yap ZhY, Efthymiou S, Seiffert S, Vargas Parra K, Lee S, Nasca A, et al. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia. Am J Hum Genet. 2021;108(12):2368-84. [DOI:10.1016/j.ajhg.2021.11.003]
15. Jian X, Boerwinkle E, Liu X. In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res. 2014;42(22):13534-44. [DOI:10.1093/nar/gku1206]
16. Richards S, Aziz N, Bale Sh, Bick D, Das S, Gastier-Foster J, et al. 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. 2015;17(5):405-24. [DOI:10.1038/gim.2015.30]
17. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073-81. [DOI:10.1038/nprot.2009.86]
18. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-9. [DOI:10.1038/nmeth0410-248]
19. Abd-Elsalam KA. Bioinformatic tools and guideline for PCR primer design. African J Biotechnol. 2003;2(5):91-5. [DOI:10.5897/AJB2003.000-1019]
20. Lampe AK, Bushby KMD. Collagen VI related muscle disorders. J Med Genet. 2005;42(9):673-85. [DOI:10.1136/jmg.2002.002311]
21. Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider Th, et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018;5(12):1574-87. [DOI:10.1002/acn3.649]
22. Becker AKA, Mikolajek H, Paulsson M, Wagener R, Werner JM. A structure of a collagen VI VWA domain displays N and C termini at opposite sides of the protein. Structure. 2014;22(2):199-208. [DOI:10.1016/j.str.2013.06.028]
23. Francomano CA, Cutting GR, McCormick MK, Chu ML, Timpl R, Hong HK, et al. The COL6A1 and COL6A2 genes exist as a gene cluster and detect highly informative DNA polymorphisms in the telomeric region of human chromosome 21q. Hum genet. 1991;87(2):162-6. [DOI:10.1007/BF00204174]
24. Cutting GR, Kazazian Jr H, Antonarakis SE, Killen PD, Yamada Y, Francomano CA. Macrorestriction mapping of COL4A1 and COL4A2 collagen genes on human chromosome 13q34. Genomics. 1988;3(3):256-63. [DOI:10.1016/0888-7543(88)90086-9]
25. Tsipouras P, Schwartz RC, Liddell AC, Salkeld CS, Weil D, Ramirez F. Genetic distance of two fibrillar collagen loci, COL3A1 and COL5A2, located on the long arm of human chromosome 2. Genomics. 1988;3(3):275-7. [DOI:10.1016/0888-7543(88)90089-4]
26. Foley AR, Hu Y, Zou Y, Columbus A, Shoffner J, Dunn DM, et al. Autosomal recessive inheritance of classic Bethlem myopathy. Neuromuscul disord. 2009;19(12):813-7. [DOI:10.1016/j.nmd.2009.09.010]
27. Westra D, Schouten MI, Stunnenberg BC, Kusters B, Saris ChGJ, Erasmus CE, et al. Panel-based exome sequencing for neuromuscular disorders as a diagnostic service. J Neuromuscul Dis. 2019;6(2):241-58. [DOI:10.3233/JND-180376]
28. Ball S, Bella J, Kielty C, Shuttleworth A. Structural basis of type VI collagen dimer formation. J Biol Chem. 2003;278(17):15326-32. [DOI:10.1074/jbc.M209977200]
29. Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M, et al. Autosomal recessive Bethlem myopathy. Neurology. 2009;73(22):1883-91. [DOI:10.1212/WNL.0b013e3181c3fd2a]
30. Fan Y, Liu A, Wei C, Yang H, Chang X, Wang S, et al. Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies. Clin Genet. 2018;93(6):1159-71. [DOI:10.1111/cge.13230]
31. Hicks D, Lampe AK, Barresi R, Charlton R, Fiorillo C, Bonnemann CG, et al. A refined diagnostic algorithm for Bethlem myopathy. Neurology. 2008;70(14):1192-9. [DOI:10.1212/01.wnl.0000307749.66438.6d]
32. Foley AR, Quijano-Roy S, Collins J, Straub V, McCallum M, Deconinck N, et al. Natural history of pulmonary function in collagen VI-related myopathies. Brain. 2013;136(Pt 12):3625-33. [DOI:10.1093/brain/awt284]
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