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A splice altering variant in NDRG1 gene causes Charcot-Marie-Tooth disease, type 4D

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Abstract

Charcot-Marie-Tooth disease, type 4D (CMT4D) is a progressive, autosomal recessive form of CMT, characterized by distal muscle weakness and atrophy, foot deformities, severe motor sensory neuropathy, and sensorineural hearing impairment. Mutations in NDRG1 gene cause neuropathy in humans, dogs, and rodents. Here, we describe clinical and genetic features of a 17-year-old male with wasting of hand muscle and foot and severe motor neuropathy. Whole exome sequencing was carried out on the patient and his unaffected parents. We identified a novel deletion of nine nucleotides (c.537 + 2_537 + 10del) on the splice donor site of intron 8 in NDRG1 gene. The Sanger sequencing confirmed the segregation of this mutation in autosomal recessive inheritance. Furthermore, transcript analysis confirmed a splice defect and reveals using of an alternate cryptic splice donor site on the downstream intronic region. It resulted in an insertion of 42 nucleotides to exon 8 of NDRG1. Translation of the resulting transcript sequence revealed an insertion of 14 amino acids in-frame to the existing NDRG1 protein. This insertion is predicted to disrupt an alpha helix which is involved in protein-protein interactions in homologous proteins. Our study expands the clinical and genetic spectrum of CMT4D. The splice defect we found in this patient reveals a novel splice isoform of NDRG1 as the potential cause for the neuropathy observed in this patient.

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Data availability

The data in this study is available with the corresponding author upon reasonable request. The data is not publicly available due to the patient’s privacy and ethical considerations.

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Acknowledgements

We thank the patient and his parents for providing consent to participate in this study.

Funding

This study was funded by Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India (EMR/2017/004853) to carry out this study and research fellowship for Prashant Phulpagar.

Author information

Author notes

  1. Pooja Pravinbabu, Vikram V Holla and Prashant Phulpagar are contributed equally to this work.

Authors and Affiliations

  1. Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India

    Pooja Pravinbabu, Prashant Phulpagar & Babylakshmi Muthusamy

  2. Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

    Vikram V. Holla, Nitish Kamble, Manjunath Netravathi, Ravi Yadav & Pramod Kumar Pal

  3. Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India

    Prashant Phulpagar & Babylakshmi Muthusamy

Authors
  1. Pooja Pravinbabu
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Contributions

Babylakshmi Muthusamy and Pramod Kumar Pal conceived and designed the study. Sample collection, processing, data analysis, and interpretation of the results were performed by Babylakshmi Muthusamy. Experiments were performed by Pooja Pravinbabu and Prashant Phulpagar. First draft of manuscript and figure illustrations were prepared by Pooja Pravinbabu and Vikram V Holla. Pramod Kumar Pal, Vikram V Holla, Manjunath Netravati, Ravi Yadav, and Nitish Kamble performed clinical assessment of the patient and provided samples. All authors reviewed the manuscript, provided critical comments to improve the draft, and approved the final version of the manuscript.

Corresponding authors

Correspondence to Pramod Kumar Pal or Babylakshmi Muthusamy.

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Ethical approval

This study was approved by the ethics committee at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore.

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This study was performed after getting appropriate informed consents from the patient and relatives.

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We obtained informed written consent from the patient and his relatives to publish this study.

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The authors declare no competing interests.

Research involving human participants and/or animals

This study involves human participants. This study was approved by the ethics committee at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore.

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Pravinbabu, P., Holla, V.V., Phulpagar, P. et al. A splice altering variant in NDRG1 gene causes Charcot-Marie-Tooth disease, type 4D. Neurol Sci 43, 4463–4472 (2022). https://doi.org/10.1007/s10072-022-05893-4

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  • DOI: https://doi.org/10.1007/s10072-022-05893-4

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