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Novel HEXA Mutation and Its Impact on Hexosaminidase-A Activity in a Heterozygous Carrier: Insight from In-vitro and In-silico study | ||
| Journal of Epigenetics | ||
| مقاله 4، دوره 6، شماره 1، شهریور 2025، صفحه 39-46 اصل مقاله (482.84 K) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22111/jep.2025.52318.1091 | ||
| نویسندگان | ||
| Ali Abolhasanzadeh Parizi1؛ Milad Lagzian* 2 | ||
| 1M.Sc graduate in Biochemistry, Dept. of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran. | ||
| 2Dept. of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran. | ||
| چکیده | ||
| Tay-Sachs disease (TSD) is a severe autosomal recessive neurodegenerative disorder resulting from mutations in the HEXA gene, leading to β-hexosaminidase A (Hex-A) deficiency. Accurate carrier identification through genetic screening is crucial for reproductive planning. This study aimed to characterize a novel HEXA variant found during preconception screening. A 30-year-old Iranian woman, whose husband is a known HEXA carrier, underwent whole-exome sequencing (WES). A novel heterozygous HEXA variant, c.[649T>C;650G>C] resulting in p.Trp203Pro, was identified in exon 6 and confirmed by Sanger sequencing. Its potential pathogenicity was assessed using in silico prediction tools (SIFT, PolyPhen-2, MutationTaster) and structural stability analysis (Molecular Dynamics and FoldX). Serum Hex-A enzyme activity was measured fluorometrically. The p.Trp203Pro variant was absent from ClinVar, HGMD, and gnomAD databases, indicating its novelty. In silico analyses consistently predicted the variant as "damaging" or "deleterious". Structural analysis predicted significant protein destabilization (ΔΔG +17.03 kcal/mol), comparable to many known pathogenic infantile-onset mutations. The patient serum Hex-A activity was 54.2% of total hexosaminidase activity, falling within the established range for heterozygous carriers. The comprehensive analysis strongly suggests that the novel p.Trp203Pro HEXA variant is likely pathogenic leading to reduced enzyme activity consistent with carrier status. This finding underscores the importance of thorough investigation of novel variants for accurate genetic counseling and highlights the expanding mutational spectrum of HEXA. | ||
| کلیدواژهها | ||
| HEXA gene؛ Tay-Sachs disease؛ Novel mutation؛ Carrier screening؛ Mutation | ||
| مراجع | ||
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Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010). A method and server for predicting damaging missense mutations. Nature Methods, 7(4), 248–249. https://doi.org/10.1038/nmeth0410-248
Bley, A. E., Giannikopoulos, O. A., Hayden, D., Kubilus, K., Tifft, C. J., & Eichler, F. S. (2011). Natural history of infantile G(M2) gangliosidosis. Pediatrics, 128(5), e1233–1241. https://doi.org/10.1542/peds.2011-0078
Demir, S. A., Timur, Z. K., Ateş, N., Martínez, L. A., & Seyrantepe, V. (2020). GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease. J Neuroinflammation, 17(1), 277. https://doi.org/10.1186/s12974-020-01947-6
Dersh, D., Iwamoto, Y., & Argon, Y. (2016). Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation. Mol Biol Cell, 27(24), 3813–3827. https://doi.org/10.1091/mbc.E16-01-0012
Edwards, S., & Laing, N. (2022). Genetic Counselling Needs for Reproductive Genetic Carrier Screening: A Scoping Review. J Pers Med, 12(10). https://doi.org/10.3390/jpm12101699
Fernández-Pereira, C., San Millán-Tejado, B., Gallardo-Gómez, M., Pérez-Márquez, T., Alves-Villar, M., Melcón-Crespo, C., Fernández-Martín, J., & Ortolano, S. (2021). Therapeutic Approaches in Lysosomal Storage Diseases. Biomolecules, 11(12). https://doi.org/10.3390/biom11121775
Gerasimavicius, L., Liu, X., & Marsh, J. A. (2020). Identification of pathogenic missense mutations using protein stability predictors. Scientific Reports, 10(1), 15387. https://doi.org/10.1038/s41598-020-72404-w
Ghosh, R., Oak, N., & Plon, S. E. (2017). Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Biology, 18(1), 225. https://doi.org/10.1186/s13059-017-1353-5
Gu, S., Yuan, B., Jabs, E. W., & Eng, C. M. (2024). Chapter 2 - Basic Principles of Genetics and Genomics. In A. D. Kline & E. W. Jabs (Eds.), Genomics in the Clinic (pp. 5–28). Academic Press. https://doi.org/https://doi.org/10.1016/B978-0-12-816478-5.00002-9
Haghighi, A., Rezazadeh, J., Shadmehri, A. A., Haghighi, A., Kornreich, R., & Desnick, R. J. (2011). Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population. J Hum Genet, 56(9), 682–684. https://doi.org/10.1038/jhg.2011.78
Jamali, S., Eskandari, N., Aryani, O., Salehpour, S., Zaman, T., Kamalidehghan, B., & Houshmand, M. (2014). Three novel mutations in Iranian patients with Tay-Sachs disease. Iran Biomed J, 18(2), 114–119. https://doi.org/10.6091/ibj.1137.2013
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., Bridgland, A., Meyer, C., Kohl, S. A. A., Ballard, A. J., Cowie, A., Romera-Paredes, B., Nikolov, S., Jain, R., Adler, J.,…Hassabis, D. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596(7873), 583–589. https://doi.org/10.1038/s41586-021-03819-2
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., Gauthier, L. D., Brand, H., Solomonson, M., Watts, N. A., Rhodes, D., Singer-Berk, M., England, E. M., Seaby, E. G., Kosmicki, J. A.,…Genome Aggregation Database, C. (2020). The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 581(7809), 434–443. https://doi.org/10.1038/s41586-020-2308-7
Krieger, E., & Vriend, G. (2014). YASARA View - molecular graphics for all devices - from smartphones to workstations. Bioinformatics, 30(20), 2981–2982. https://doi.org/10.1093/bioinformatics/btu426
Landrum, M. J., Lee, J. M., Benson, M., Brown, G. R., Chao, C., Chitipiralla, S., Gu, B., Hart, J., Hoffman, D., Jang, W., Karapetyan, K., Katz, K., Liu, C., Maddipatla, Z., Malheiro, A., McDaniel, K., Ovetsky, M., Riley, G., Zhou, G.,…Maglott, D. R. (2018). ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res, 46(D1), D1062–d1067. https://doi.org/10.1093/nar/gkx1153
Leal, A. F., Benincore-Flórez, E., Solano-Galarza, D., Garzón Jaramillo, R. G., Echeverri-Peña, O. Y., Suarez, D. A., Alméciga-Díaz, C. J., & Espejo-Mojica, A. J. (2020). GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies. Int J Mol Sci, 21(17). https://doi.org/10.3390/ijms21176213
Mehta, N., Lazarin, G. A., Spiegel, E., Berentsen, K., Brennan, K., Giordano, J., Haque, I. S., & Wapner, R. (2016). Tay-Sachs Carrier Screening by Enzyme and Molecular Analyses in the New York City Minority Population. Genet Test Mol Biomarkers, 20(9), 504–509. https://doi.org/10.1089/gtmb.2015.0302
Neudorfer, O., Pastores, G. M., Zeng, B. J., Gianutsos, J., Zaroff, C. M., & Kolodny, E. H. (2005). Late-onset Tay-Sachs disease: Phenotypic characterization and genotypic correlations in 21 affected patients. Genetics in Medicine, 7(2), 119–123. https://doi.org/10.1097/01.GIM.0000154300.84107.75
Ng, P. C., & Henikoff, S. (2003). SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res, 31(13), 3812–3814. https://doi.org/10.1093/nar/gkg509
Rehm, H. L., Bale, S. J., Bayrak-Toydemir, P., Berg, J. S., Brown, K. K., Deignan, J. L., Friez, M. J., Funke, B. H., Hegde, M. R., & Lyon, E. (2013). ACMG clinical laboratory standards for next-generation sequencing. Genet Med, 15(9), 733–747. https://doi.org/10.1038/gim.2013.92
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., & Rehm, H. L. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 17(5), 405–424. https://doi.org/10.1038/gim.2015.30
Richardson, E., McEwen, A., Newton-John, T., Crook, A., & Jacobs, C. (2022). Systematic review of outcomes in studies of reproductive genetic carrier screening: Towards development of a core outcome set. Genetics in Medicine, 24(1), 1–14. https://doi.org/https://doi.org/10.1016/j.gim.2021.08.005
Rozenberg, R., & Pereira Lda, V. (2001). The frequency of Tay-Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program. Sao Paulo Med J, 119(4), 146–149. https://doi.org/10.1590/s1516-31802001000400007
Rudnik-Schöneborn, S., & Zerres, K. (2022). Preconception carrier screening as an alternative reproductive option prior to newborn screening for severe recessive disorders. Med Genet, 34(2), 157–161. https://doi.org/10.1515/medgen-2022-2123
Saadat, M., Ansari-Lari, M., & Farhud, D. D. (2004). Consanguineous marriage in Iran. Ann Hum Biol, 31(2), 263–269. https://doi.org/10.1080/03014460310001652211
Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., & Serrano, L. (2005). The FoldX web server: an online force field. Nucleic Acids Res, 33(Web Server issue), W382–388. https://doi.org/10.1093/nar/gki387
Specola, N., Vanier, M. T., Goutières, F., Mikol, J., & Aicardi, J. (1990). The juvenile and chronic forms of GM2 gangliosidosis: clinical and enzymatic heterogeneity. Neurology, 40(1), 145–150. https://doi.org/10.1212/wnl.40.1.145
Steinhaus, R., Proft, S., Schuelke, M., Cooper, D. N., Schwarz, J. M., & Seelow, D. (2021). MutationTaster2021. Nucleic Acids Res, 49(W1), W446–w451. https://doi.org/10.1093/nar/gkab266
Stenson, P. D., Mort, M., Ball, E. V., Chapman, M., Evans, K., Azevedo, L., Hayden, M., Heywood, S., Millar, D. S., Phillips, A. D., & Cooper, D. N. (2020). The Human Gene Mutation Database (HGMD(®)): optimizing its use in a clinical diagnostic or research setting. Hum Genet, 139(10), 1197–1207. https://doi.org/10.1007/s00439-020-02199-3
Suzuki, K. (1987). Enzymatic diagnosis of sphingolipidoses. Methods Enzymol, 138, 727–762. https://doi.org/10.1016/0076-6879(87)38063-2
Wakamatsu, N., Benoit, G., Lamhonwah, A. M., Zhang, Z. X., Trasler, J. M., Triggs-Raine, B. L., & Gravel, R. A. (1994). Structural organization, sequence, and expression of the mouse HEXA gene encoding the alpha subunit of hexosaminidase A. Genomics, 24(1), 110–119. https://doi.org/10.1006/geno.1994.1587 | ||
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