Novel mutation in PLP1 gene in an individual with Pelizaeus-Merzbacher disease (PMD) using whole exome sequencing

Document Type : Original Article

Authors

1 Department of Biotechnology, Ahv.C., Islamic Azad University, Ahvaz, Iran.

2 Department of Fisheries, Ahv.C., Islamic Azad University, Ahvaz, Iran.

Abstract

Background: Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system. This disease is associated with abnormalities of the white matter of the brain and spinal cord. It is a subgroup of leukodystrophies caused by abnormalities in one or more components (mainly fat or protein) that contribute to the formation of the white matter (myelin sheath) of the brain. Point mutations account for the remaining 20% of cases and are associated with highly variable phenotypes. These cases can range from mild to severe congenital clinical forms. Case Presentation: A family with one affected person studied in Baghdad, Iraq. The causative gene identified by exome sequencing. Exome sequencing results showed that a c.772A > C; p. Met258Leu mutation exists in the affected son of this family. To confirm the presence of the pathogenic PLP1 mutation, we performed direct Sanger sequencing on the patient and his mother. He was a hemizygous for this mutation while his mother was heterozygous. Conclusion: Our findings broaden the range of pathogenic mutations in PLP1 associated with the PMD disease, which is essential for the disease's genetic diagnosis and screening. This finding supports earlier studies indicating a connection between mutations in the PLP1 gene and PMD. Our research can assist in offering proper genetic counseling to the families impacted and helps enhance our understanding of how the PLP1 gene functions in PMD.

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References

Alghamdi, Malak, Essa Alharbi, Salman Aljarallah, Ghaida Alghamdi, Reham M Balahmar, Nisserin Jado, Hebattalah Hamed, Dima Jamjoom, Fahad A Bashiri, and Naif AM Almontashiri. 2025. 'A copy number variant overlapping the 3ʹUTR of PLP1 causes spastic paraplegia', Journal of Human Genetics: 1-6.
Boudellioua, Imane, Maxat Kulmanov, Paul N Schofield, Georgios V Gkoutos, and Robert Hoehndorf. 2019. 'DeepPVP: phenotype-based prioritization of causative variants using deep learning', BMC bioinformatics, 20: 1-8.
Cambi, F, X-M Tang, P Cordray, PR Fain, LD Keppen, and DF Barker. 1996. 'Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia', Neurology, 46: 1112-17.
Cornish, Alex J, Alessia David, and Michael JE Sternberg. 2018. 'PhenoRank: reducing study bias in gene prioritization through simulation', Bioinformatics, 34: 2087-95.
Duan, Ruoyu, Haoran Ji, Huifang Yan, Junyu Wang, Yu Zhang, Qian Zhang, Dongxiao Li, Binbin Cao, Qiang Gu, and Ye Wu. 2022. 'Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease', Orphanet Journal of Rare Diseases, 17: 137.
Elitt, Matthew S, and Paul J Tesar. 2024. 'Pelizaeus–Merzbacher disease: on the cusp of myelin medicine', Trends in Molecular Medicine.
Gonzaga-Jauregui, Claudia, Tamar Harel, Tomasz Gambin, Maria Kousi, Laurie B Griffin, Ludmila Francescatto, Burcak Ozes, Ender Karaca, Shalini N Jhangiani, and Matthew N Bainbridge. 2015. 'Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy', Cell reports, 12: 1169-83.
Hobson, Grace M, and James Y Garbern. 2012. "Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders." In Seminars in neurology, 062-67. Thieme Medical Publishers.
Koeppen, Arnulf H, and Yves Robitaille. 2002. 'Pelizaeus-merzbacher disease', Journal of Neuropathology & Experimental Neurology, 61: 747-59.
Köhler, Sebastian, Nicole A Vasilevsky, Mark Engelstad, Erin Foster, Julie McMurry, Ségolène Aymé, Gareth Baynam, Susan M Bello, Cornelius F Boerkoel, and Kym M Boycott. 2017. 'The human phenotype ontology in 2017', Nucleic acids research, 45: D865-D76.
Lyahyai, Jaber, Bouchra Ouled Amar Bencheikh, Siham C Elalaoui, Maria Mansouri, Lamia Boualla, Alexandre DIonne-Laporte, Dan Spiegelman, Patrick A Dion, Patrick Cossette, and Guy A Rouleau. 2018. 'Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report', BMC pediatrics, 18: 1-4.
Osório, M Joana, and Steven A Goldman. 2018. 'Neurogenetics of Pelizaeus–Merzbacher disease', Handbook of clinical neurology, 148: 701-22.
Sarmadi, Akram, Aliasgar Mohammadi, Fatemeh Tabatabaei, Zahra Nouri, Morteza Hashemzadeh Chaleshtori, and Mohammad Amin Tabatabaiefar. 2020. 'Molecular genetic study in a cohort of Iranian families suspected to maturity-onset diabetes of the young, reveals a recurrent mutation and a high-risk variant in the CEL gene', Advanced biomedical research, 9: 25.
Schlüter, Agatha, Agustí Rodríguez-Palmero, Edgard Verdura, Valentina Vélez-Santamaría, Montserrat Ruiz, Stéphane Fourcade, Laura Planas-Serra, Juan José Martínez, Cristina Guilera, and Marisa Girós. 2022. 'Diagnosis of genetic white matter disorders by singleton whole-exome and genome sequencing using interactome-driven prioritization', Neurology, 98: e912-e23.
Sherman, Larry S, Weiping Su, Amanda L Johnson, Samuel M Peterson, Cassandra Cullin, Tiffany Lavinder, Betsy Ferguson, and Anne D Lewis. 2021. 'A novel non-human primate model of Pelizaeus-Merzbacher disease', Neurobiology of disease, 158: 105465.
Shiihara, Takashi, Mio Watanabe, Kengo Moriyama, Mitsugu Uematsu, and Kiyoko Sameshima. 2015. 'A novel PLP1 frameshift mutation causing a milder form of Pelizaeus–Merzbacher disease', Brain and Development, 37: 455-58.
van De Warrenburg, Bart P, Meyke I Schouten, Susanne T de Bot, Sascha Vermeer, Rowdy Meijer, Maartje Pennings, Christian Gilissen, Michèl AAP Willemsen, Hans Scheffer, and Erik-Jan Kamsteeg. 2016. 'Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene–disease associations and unanticipated rare disorders', European Journal of Human Genetics, 24: 1460-66.
Vanderver, Adeline, Cas Simons, Guy Helman, Joanna Crawford, Nicole I Wolf, Genevieve Bernard, Amy Pizzino, Johanna L Schmidt, Asako Takanohashi, and David Miller. 2016. 'Whole exome sequencing in patients with white matter abnormalities', Annals of neurology, 79: 1031-37.
Yang, Hui, Peter N Robinson, and Kai Wang. 2015. 'Phenolyzer: phenotype-based prioritization of candidate genes for human diseases', Nature methods, 12: 841-43.
Journal of Epigenetics
Volume 6, Issue 1
June 2025
Pages 64-69

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History

  • Receive Date: 19 May 2025
  • Revise Date: 11 June 2025
  • Accept Date: 25 June 2025

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