A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular
Dysfunctions Found by Whole Exome Sequencing and In Silico Analyses in
an Iranian Family

Vahid      Omarmeli; Kai-Uwe      Lewandrowski; Marjan      Assefi; Hanieh      Faizmahdavi; Alireza      Sharafshah; Nasrin      Mansouri

doi:10.2174/0118746098280408240112112414

Abstract

Background: Duchene Muscular Disorder (DMD) is a severe X-linked recessive neuromuscular disease. Previous reports predicted that one-third of cases with a fatal X-linked recessive disease will be caused by a novel mutation, and the mutation rate for DMD seems to be higher in males.

Objective: A novel mutation in the DMD gene DMD (NM_004006.3):c.92A>G (p.Lys31Arg) is suggested for males because of their heterozygous mothers carrying the mutant alleles.

Method: Whole Exome Sequencing (WES) was done for a 25-year-old female followed by the screening of the novel mutation in her parents and her brother by the Sanger sequencing technique. Some in silico analyses were run to find the putative alterations in wild-type and mutant structures by PolyPhen-2 and Mupro. Notably, SWISS-MODEL was performed to build a reliable model for the mutant allele based on the PDB ID: 1DXX structure. Also, superimposition was done by PyMol.

Results: WES analysis revealed three novel mutations including DLD (exon13:c.G1382A:p. G461E), ABCA3 (exon12:c.G1404C:p.W468C), and DMD (exon2:c.A92G:p.K31R) in the case. Focusing on DMD mutation, Sanger sequencing of the patient’s parents and brother indicated no mutant allele in her mother and brother but a mutant allele in her father as a hemizygous pattern. In silico analyses showed no considerable change regarding pathogenic impact.

Conclusion: In conclusion, our findings revealed no pathogenic effect of the new mutation (K31R) of the DMD gene in an Iranian 25-year-old woman. Because of the DMD importance in preclinical diagnosis, these data may shed a light on the diagnosis of this mutation in future pregnancies.

Keywords: Whole exome sequencing, DMD, mutation, in silico, K31R, neuromuscular dysfunctions.

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[1]
Chung J, Smith AL, Hughes SC, et al. Twenty‐year follow‐up of newborn screening for patients with muscular dystrophy. Muscle Nerve  2016; 53(4): 570-8.
 [http://dx.doi.org/10.1002/mus.24880] [PMID:  26260293]

[2]
Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: The protein product of the duchenne muscular dystrophy locus. Cell  1987; 51(6): 919-28.
 [http://dx.doi.org/10.1016/0092-8674(87)90579-4] [PMID:  3319190]

[3]
Pane M, Scalise R, Berardinelli A, et al. Early neurodevelopmental assessment in Duchenne muscular dystrophy. Neuromuscul Disord  2013; 23(6): 451-5.
 [http://dx.doi.org/10.1016/j.nmd.2013.02.012] [PMID:  23535446]

[4]
Ferlini A, Neri M, Gualandi F. The medical genetics of dystrophinopathies: Molecular genetic diagnosis and its impact on clinical practice. Neuromuscul Disord  2013; 23(1): 4-14.
 [http://dx.doi.org/10.1016/j.nmd.2012.09.002] [PMID:  23116935]

[5]
Findlay AR, Wein N, Kaminoh Y, et al. Clinical phenotypes as predictors of the outcome of skipping aroundDMD exon 45. Ann Neurol  2015; 77(4): 668-74.
 [http://dx.doi.org/10.1002/ana.24365] [PMID:  25612243]

[6]
Ogura Y, Tajrishi MM, Sato S, Hindi SM, Kumar A. Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy. Front Cell Dev Biol  2014; 2: 11.
 [http://dx.doi.org/10.3389/fcell.2014.00011] [PMID:  25364719]

[7]
Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. Lancet  2011; 378(9791): 595-605.
 [http://dx.doi.org/10.1016/S0140-6736(11)60756-3] [PMID:  21784508]

[8]
Haldane JBS. The rate of spontaneous mutation of a human gene. J Genet  1935; 31(3): 317-26.
 [http://dx.doi.org/10.1007/BF02982403] [PMID:  15689625]

[9]
Haldane BJBS. Mutation in the sex-linked recessive type of muscular dystrophy; a possible sex difference. Ann Hum Genet  1956; 20(4): 344-7.
 [http://dx.doi.org/10.1111/j.1469-1809.1955.tb01289.x] [PMID:  13314403]

[10]
Prior TW, Papp AC, Snyder PJ, et al. A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient. Nat Genet  1993; 4(4): 357-60.
 [http://dx.doi.org/10.1038/ng0893-357] [PMID:  8401582]

[11]
Prior TW, Bartolo C, Papp AC, et al. Identification of a missense mutation, single base deletion and a polymorphism in the dystrophin exon 16. Hum Mol Genet  1994; 3(7): 1173-4.
 [http://dx.doi.org/10.1093/hmg/3.7.1173] [PMID:  7981690]

[12]
Saad FA, Vita G, Toffolatti L, Danieli GA. A possible missense mutation detected in the dystrophin gene by double strand conformation analysis (DSCA). Neuromuscul Disord  1994; 4(4): 335-41.
 [http://dx.doi.org/10.1016/0960-8966(94)90069-8] [PMID:  7981590]

[13]
Goldberg LR, Hausmanowa-Petrusewicz I, Fidzianska A, Duggan DJ, Steinberg LS, Hoffman EP. A dystrophin missense mutation showing persistence of dystrophin and dystrophin‐associated proteins yet a severe phenotype. Ann Neurol  1998; 44(6): 971-6.
 [http://dx.doi.org/10.1002/ana.410440619] [PMID:  9851445]

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DOI https://dx.doi.org/10.2174/0118746098280408240112112414	Print ISSN 1874-6098
Publisher Name Bentham Science Publisher	Online ISSN 1874-6128

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A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular Dysfunctions Found by Whole Exome Sequencing and In Silico Analyses in an Iranian Family

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