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A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family

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Abstract

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in DMD gene effecting the expression of dystrophin. Generally female carriers are asymptomatic; however, it has been suggested that carriers may exhibit symptoms. We investigated a 6-year-old Chinese girl exhibiting a suspected BMD phenotype, including persistently elevated creatine kinase and creatine kinase isoenzyme levels. The proband harbored a novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene inherited from her mother who had a completely normal phenotype and presented with mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]. In addition, X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%. Amplification of regions of the cDNA revealed different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%. Real-time PCR showed that mRNA expression was significantly decreased in both. We proposed that a frameshift or nonsense mutation may contribute to the development of symptoms in carriers. These phenotypes correlate with nonrandom XCI patterns and are compounded by the locus of the mutation. For incompletely skewed XCI patterns, although the mutant allele could suppress the expression of a normal allele, carriers would remain asymptomatic as long as there was adequate compensation from the normal allele. We also proposed a mechanism where mRNA from the mutant allele may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.

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Funding

This work was supported by a grant from the National Natural Science Foundation of China (31970558), the Natural Science Foundation of Guangdong Province (2018B030311033), the Science and Technology Program of Guangzhou (201707010301) and the Foundation of President of Nanfang Hospital (2018B003).

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Author notes

  1. Jianfan Chen and Hui Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People’s Republic of China

    Jianfan Chen, Zhongju Wang, Jian Wang, Fei He & Fu Xiong

  2. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China

    Hui Zheng

  3. Department of Neurology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Cheng Zhang

  4. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong Province, People’s Republic of China

    Fei He & Fu Xiong

Authors
  1. Jianfan Chen
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  2. Hui Zheng
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  3. Zhongju Wang
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  4. Jian Wang
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  5. Fei He
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  6. Cheng Zhang
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  7. Fu Xiong
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Contributions

FX and X-MX initiated the study FX and HZ designed and oversaw the entire project. CZ recruited patients and performed clinical evaluation and sample collection. J-FC, Z-JW and JW performed function analysis. J-FC prepared the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fu Xiong.

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Conflict of interest

The authors declare that they have no conflict of interest. This study involved Human Participants, and was approved by the Southern University ethics committee. Informed consent was obtained from patients and relatives before analysis.

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Communicated by Stefan Hohmann.

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Chen, J., Zheng, H., Wang, Z. et al. A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family. Mol Genet Genomics 296, 541–549 (2021). https://doi.org/10.1007/s00438-020-01757-8

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  • DOI: https://doi.org/10.1007/s00438-020-01757-8

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