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C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN)

European Journal of Human Genetics volume 33, pages 878–886 (2025)Cite this article

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Abstract

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurodegenerative disorder characterized by spastic paraplegia, parkinsonism and psychiatric and/or behavioral symptoms caused by variants in gene encoding chromosome-19 open reading frame-12 (C19orf12). We present here seven patients from six unrelated families with detailed clinical, radiological, and genetic investigations. Childhood-onset patients predominantly had a spastic ataxic phenotype with optic atrophy, while adult-onset patients were presented with cognitive, behavioral, and parkinsonian symptoms. Levodopa induced choreiform dyskinesia was observed in one patient who showed a response to levodopa. Brain magnetic resonance imaging showed mineralization in all patients and cerebellar atrophy in one patient. The “pallidal splitting sign” was found in two patients and additional caudate and putamen mineralization was noted in two patients. Exome sequencing identified six variants in the C19orf12 gene, including two novel splice-site variants, four previously reported missense variants. Transcript analysis using RT-PCR followed by Sanger sequencing was performed on a splice site variant (c.194-2delA) to understand the splice defect and its consequences. This analysis confirmed the splice defect and use of an alternate cryptic splice site in the downstream exonic region. The variants identified in this study expand the spectrum of clinical and genetic knowledge on MPAN patients, highlighting the importance of genetic testing in the diagnosis and management of this disorder.

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Fig. 1: MRI Brain of the patients.
Fig. 2: Visualization and Sanger sequencing of identified variants in patients and family members.
Fig. 3: Transcript analysis of c.194-2delA variant.

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Data availability

The data is available with the corresponding author with reasonable request.

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Acknowledgements

We thank the patients and their families to participating in this study.

Funding

This study is funded for a research project (54/12/2019-HUM/BMS) from the Indian Council of Medical Research (ICMR), New Delhi. Riyanka Kumari is a recipient of Senior Research Fellowship from CSIR, Government of India.

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Author notes

  1. These authors contributed equally: Riyanka Kumari, Vikram V. Holla, Neeharika Sriram.

Authors and Affiliations

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

    Riyanka Kumari & Babylakshmi Muthusamy

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

    Riyanka Kumari

  3. Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, 560029, India

    Vikram V. Holla, Neeharika Sriram, Nitish Kamble, Ajay Asranna, Ravi Yadav & Pramod Kumar Pal

  4. Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, 560029, India

    Jitender Saini

  5. Department of Human Genetics, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, 560029, India

    Gautham Arunachal

  6. Department of Laboratory Medicine and Pathology, Rochester, MN, USA

    Akhilesh Pandey

  7. Center for Individualized Medicine Mayo Clinic, Rochester, MN, USA

    Akhilesh Pandey

  8. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

    Babylakshmi Muthusamy

Authors
  1. Riyanka Kumari
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Contributions

PKP; VVH; NS; NK; AA; RY; JS:- clinical assessments, radiological investigations, manuscript review. BM; VVH; GA; RK:- data analysis, BM; RK; VVH:- results interpretation, wrote initial draft of the manuscript review. All authors: Review and critical input to improve the manuscript.

Corresponding authors

Correspondence to Pramod Kumar Pal or Babylakshmi Muthusamy.

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The authors declare no competing interests.

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This study was approved by the institutional ethics committee at NIMHANS, Bangalore.

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Kumari, R., Holla, V.V., Sriram, N. et al. C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN). Eur J Hum Genet 33, 878–886 (2025). https://doi.org/10.1038/s41431-024-01778-6

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