A NOVEL MISSENSE MUTATION (C.1982A>C) IN FCHSD1 GENE CAUSES AUTOSOMAL RECESSIVE EARLY ONSET PARKINSON’S DISEASE IN A CONSANGUINEOUS PAKISTANI FAMILY

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Muhammad Umair
Muhammad Iqbal
Ghulam Mustafa
Munir Ahmad Bhinder
Muhammad Zuhaib Shah
Shahbaz Khan
Razia Parveen
Amir Ejaz
Hafiz Muhammad Azhar Baig

Keywords

Parkinson’s disease, FCHSD1, mTOR, Whole Exome Sequencing, Autosomal Recessive, Early Onset Parkinson disease

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized mainly by degenerative loss
of dopamine producing neurons and accumulation of alpha synuclein in substantia nigra pars
compacta (SNpc) of midbrain. Impairment of autophagy is believed to be common among multiple
neurodegenerative disorders. The disruption in autophagic process and improper removal of
accumulated proteins are linked with various neurodegenerative disorders including Parkinson’s
disease. Whole Exome Sequencing (WES) was done on extracted DNA of the patient having PD to
identify novel causative variants for underlying disorder. Identified variant was then validated in
other family members through Sanger’s sequencing. A novel missense variant
NM_033449.3:c.1982A>C (p.Asp661Ala) in FCHSD1 gene was identified through WES.
Segregation of the mutation in other family members was confirmed through Sanger’s sequencing.
The identified mutation (c.1982A>C) in FCHSD1 gene is responsible for autosomal recessive
Parkinson’s disease in a consanguineous Pakistani family.
Background: Parkinson’s Disease (PD) is a neurodegenerative disorder characterized mainly by
degenerative loss of dopamine producing neurons and accumulation of alpha synuclein in substantia
nigra pars compacta (SNpc) of midbrain. Impairment of autophagy is believed to be common
among multiple neurodegenerative disorders. The disruption in autophagic process and improper
removal of accumulated proteins are linked with various neurodegenerative disorders including
Parkinson’s disease.
Aims: The aim of this study was to describe the genetic variants responsible for Parkinson’s
Diseases in a consanguineous family.
Objective: To identify novel causative mutation responsible for autosomal recessive Parkinson’s
disease in a consanguineous Pakistani family.
Methods: Whole Exome Sequencing was done on extracted DNA to identify novel causative variants for underlying disorder. Identified variant was then validated in other family members
through Sanger’s sequencing.
Results: A novel missense variant NM_033449.3;c.1982A>C in FCHSD1 gene was identified
through Whole Exome Sequencing (WES). Segregation of the mutation was confirmed through
Sanger’s sequencing.
Conclusion: Identified mutation (c.1982A>C) in FCHSD1 gene is responsible for autosomal
recessive Parkinson’s disease in a consanguineous Pakistani family.

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References

1. Huertas, I., Jesús, S., García-Gómez, F. J., Lojo, J. A., Bernal-Bernal, I., Bonilla-Toribio, M., ... & Mir, P. (2017). Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease. PloS one, 12(4), e0175560.
2. Fahn, S. (2008). Clinical aspects of Parkinson disease. In Parkinson's Disease (pp. 1-8). Academic Press.
3. Puspita, L., Chung, S. Y., & Shim, J. W. (2017). Oxidative stress and cellular pathologies in Parkinson’s disease. Molecular brain, 10, 1-12.
4. Dauer, W., & Przedborski, S. (2003). Parkinson's disease: mechanisms and models. Neuron, 39(6), 889-909.
5. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. cell, 149(2), 274-293
6. Fernández‐Santiago, R., Martín‐Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres‐Ciga, S., ... & Malagelada, C. (2019). SNCA and mTOR pathway single nucleotide polymorphisms interact to modulate the age at onset of Parkinson's disease. Movement Disorders, 34(9), 1333-1344.
7. Dai, C., Zhang, Y., Zhan, X., Tian, M., & Pang, H. (2021). Association Analyses of SNAP25, HNMT, FCHSD1, and DBH Single-Nucleotide Polymorphisms with Parkinson’s Disease in a Northern Chinese Population. Neuropsychiatric Disease and Treatment, 1689-1695.
8. Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124(3), 471-484.
9. Zheng, X. F., Fiorentino, D., Chen, J., Crabtree, G. R., & Schreiber, S. L. (1995). TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell, 82(1), 121-130.\
10. Kim, D. H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., ... & Sabatini, D. M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110(2), 163-175.
11. Sarbassov, D. D., Ali, S. M., Kim, D. H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., ... & Sabatini, D. M. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current biology, 14(14), 1296-1302.
12. Calabresi, P., Galletti, F., Saggese, E., Ghiglieri, V., & Picconi, B. (2007). Neuronal networks and synaptic plasticity in Parkinson's disease: beyond motor deficits. Parkinsonism & related disorders, 13, S259-S262.\
13. Xu, Y., Liu, C., Chen, S., Ye, Y., Guo, M., Ren, Q., ... & Chen, L. (2014). Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease. Cellular signalling, 26(8), 1680-1689.
14. Griffin, R. J., Moloney, A., Kelliher, M., Johnston, J. A., Ravid, R., Dockery, P., ... & O'Neill, C. (2005). Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. Journal of neurochemistry, 93(1), 105-117.
15. Malagelada, C., Jin, Z. H., & Greene, L. A. (2008). RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. Journal of Neuroscience, 28(53), 14363-14371.
16. Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S., & Greene, L. A. (2010). Rapamycin protects against neuron death in in vitro andIn vivo models of Parkinson's disease. Journal of Neuroscience, 30(3), 1166-1175.
17. Cuyàs, E., Corominas-Faja, B., Joven, J., & Menendez, J. A. (2014). Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway. Cell Cycle Control: Mechanisms and Protocols, 113-144.
18. Caccamo, A., Maldonado, M. A., Majumder, S., Medina, D. X., Holbein, W., Magrí, A., & Oddo, S. (2011). Naturally secreted amyloid-β increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. Journal of Biological Chemistry, 286(11), 8924-8932.
19. Dehay, B., Bové, J., Rodríguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010). Pathogenic lysosomal depletion in Parkinson's disease. Journal of Neuroscience, 30(37), 12535-12544.
20. Wong, Y. C., & Krainc, D. (2017). α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nature medicine, 23(2), 1-13.
21. Crews, L., Spencer, B., Desplats, P., Patrick, C., Paulino, A., Rockenstein, E., ... & Masliah, E. (2010). Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy. PloS one, 5(2), e9313.
22. Gao, S., Duan, C., Gao, G., Wang, X., & Yang, H. (2015). Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling. The international journal of biochemistry & cell biology, 64, 25-33.
23. Decressac, M., & Björklund, A. (2013). mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats. Journal of Parkinson's disease, 3(1), 13-17.
24. Heras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J., & Pedraza-Chaverri, J. (2014). The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cellular signalling, 26(12), 2694-2701.
25. Malagelada, C., Ryu, E. J., Biswas, S. C., Jackson-Lewis, V., & Greene, L. A. (2006). RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. Journal of Neuroscience, 26(39), 9996-10005.
26. Corradetti, M. N., Inoki, K., & Guan, K. L. (2005). The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. Journal of Biological Chemistry, 280(11), 9769-9772.
27. Huang, R. S., Duan, S., Shukla, S. J., Kistner, E. O., Clark, T. A., Chen, T. X., ... & Dolan, M. E. (2007). Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. The American Journal of Human Genetics, 81(3), 427-437.
28. Chacon-Cortes D, Griffiths LR. Methods for extracting genomic DNA from whole blood samples: current perspectives. Journal of Biorepository Science for Applied Medicine. 2014 May 28:1-9.
29. Wickremaratchi, M. M., Ben‐Shlomo, Y., & Morris, H. R. (2009). The effect of onset age on the clinical features of Parkinson’s disease. European journal of neurology, 16(4), 450-456.
30. Funayama, M., Nishioka, K., Li, Y., & Hattori, N. (2023). Molecular genetics of Parkinson’s disease: Contributions and global trends. Journal of Human Genetics, 68(3), 125-130.
31. Cheng, I., Sasegbon, A., & Hamdy, S. (2023). Dysphagia treatments in Parkinson's disease: A systematic review and meta‐analysis. Neurogastroenterology & Motility, 35(8), e14517.
32. Santos-García, D., de Deus Fonticoba, T., Cores Bartolomé, C., Feal Painceiras, M. J., Íñiguez-Alvarado, M. C., Jesús, S., ... & Mir, P. (2023). Prevalence and Factors Associated with Drooling in Parkinson’s Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group. Parkinson’s Disease, 2023.
33. Caballol, N., Martí, M. J., & Tolosa, E. (2007). Cognitive dysfunction and dementia in Parkinson disease. Movement disorders: official journal of the Movement Disorder Society, 22(S17), S358-S366.

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