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A Novel IGHMBP2 Missense Variant in an Iranian Family with CMT2S: Experimental and Computational Approaches | ||
| Journal of Genetic Resources | ||
| دوره 12، شماره 1، 2026، صفحه 94-106 اصل مقاله (683.27 K) | ||
| نوع مقاله: Research Article | ||
| شناسه دیجیتال (DOI): 10.22080/jgr.2026.31751.1462 | ||
| نویسندگان | ||
| Morteza Karbasi؛ Masoud Garshasbi* | ||
| Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran | ||
| تاریخ دریافت: 23 اردیبهشت 1405، تاریخ بازنگری: 25 خرداد 1405، تاریخ پذیرش: 31 خرداد 1405 | ||
| چکیده | ||
| Variants in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene are associated with two phenotypes: The first phenotype is spinal muscular atrophy with respiratory distress type 1 (SMARD1), an alpha motor neuron disorder characterized by diaphragmatic paralysis and early death, often within the first year of life. The second phenotype is Charcot-Marie-Tooth disease type 2S (CMT2S), a slowly progressive axonal neuropathy marked by sensory loss and typically lacking respiratory involvement. This study aimed to identify the genetic cause of CMT2S in an Iranian family and to review previously reported variants and clinical features of CMT2S in the literature. Exome sequencing was performed on the affected proband. The candidate variant was subsequently validated in additional family members using Sanger sequencing. The pathogenicity and novelty of the variant were assessed using in silico prediction tools and available databases. We identified a novel homozygous variant, c.509T>C (p. Leu170Pro), in the IGHMBP2 gene. 60 patients (59 patients + 1 case) were analyzed with CMT2S in our literature review. The main symptoms observed among these patients included muscle weakness and atrophy, absent reflexes, foot deformities, and gait disturbances. Atypical symptoms, including respiratory problems, gastrointestinal disturbances, and bladder dysfunction, were reported in a minority of cases. Among patients with an available age of onset, the mean age was 3.40 (SD± 3.83 years), with an interquartile range of 4.33 years. Across the analyzed patients, 98 total variants were included in the final mutational spectrum. Among these variants, c.1235+3A>G (p.Ala355Leufs*10) was the most frequently reported variant, occurring in seven patients. We report the second known case of CMT2S in a patient of Iranian descent, associated with a novel biallelic variant in the IGHMBP2 gene. Our findings, along with previous findings from the literature, expand the mutational spectrum of IGHMBP2 in CMT2S, contributing to a better understanding of its clinical and genetic heterogeneity. | ||
| کلیدواژهها | ||
| Charcot-Marie-Tooth Disease؛ CMT2S؛ Exome Sequencing؛ IGHMBP2؛ Novel variant | ||
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| مراجع | ||
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Adzhubei, I., Jordan, D. M., & Sunyaev, S. R. (2013). Predicting functional effect of human missense mutations using PolyPhen-2. Current Protocols in Human Genetics, 76(1), 7-20. https://doi.org/10.1002/0471142905.hg0720s76
Ahmed, A. N., Rawlins, L. E., Khan, N., Jan, Z., Ubeyratna, N., Voutsina, N., Azeem, A., Khan, S., Baple, E. L., Crosby, A. H., & Saleha, S. (2024). Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan. BMC Neurology, 24(1), 394. https://doi.org/10.1186/s12883-024-03882-y
Ashkenazy, H., Abadi, S., Martz, E., Chay, O., Mayrose, I., Pupko, T., & Ben-Tal, N. (2016). ConSurf 2016: An improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Research, 44(W1), W344-350. https://doi.org/10.1093/nar/gkw408
Bolger, A. M., Lohse, M., & Usadel, B. (2014). Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 30(15), 2114-2120. https://doi.org/10.1093/bioinformatics/btu170
Cassini, T. A., Duncan, L., Rives, L. C., Newman, J. H., Phillips, J. A., Koziura, M. E., Brault, J., Hamid, R., Cogan, J., & Undiagnosed Diseases, N. (2019). Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and charcot-marie-tooth phenotype with early onset symptoms. Molecular Genetics and Genomic Medicine, 7(6), e00676. https://doi.org/10.1002/mgg3.676
Chandrasekharan, S. V., Nair, S. S., Ganapathy, A., Mannan, A. U., & Sundaram, S. (2022). Charcot-marie-tooth disease type 2S: identical novel missense mutation of IGHMBP2 gene in two unrelated families. Neurological Sciences, 43(1), 719-722. https://doi.org/10.1007/s10072-021-05668-3
Cottenie, E., Kochanski, A., Jordanova, A., Bansagi, B., Zimon, M., Horga, A., Jaunmuktane, Z., Saveri, P., Rasic, V. M., Baets, J., Bartsakoulia, M., Ploski, R., Teterycz, P., Nikolic, M., Quinlivan, R., Laura, M., Sweeney, M. G., Taroni, F., Lunn, M. P. Houlden, H. (2014). Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. American Journal of Human Genetics, 95(5), 590-601. https://doi.org/10.1016/j.ajhg.2014.10.002
De Planell-Saguer, M., Schroeder, D. G., Rodicio, M. C., Cox, G. A., & Mourelatos, Z. (2009). Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Human Molecular Genetics, 18(12), 2115-2126. https://doi.org/10.1093/1hmg/ddp134
Fariselli, P., Martelli, P. L., Savojardo, C., & Casadio, R. (2015). INPS: Predicting the impact of non-synonymous variations on protein stability from sequence. Bioinformatics, 31(17), 2816-2821. https://doi.org/10.1093/bioinformatics/btv291
Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., Cannon-Albright, L. A., Teerlink, C. C., Stanford, J. L., Isaacs, W. B., Xu, J., Cooney, K. A., Lange, E. M., Schleutker, J., Carpten, J. D., Sieh, W. (2016). REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. American Journal of Human Genetics, 99(4), 877-885. https://doi.org/10.1016/j.ajhg.2016.08.016
Ipek, R., Cavdartepe, B. E., Bozdogan, S. T., Altunisik, E., Akalin, A., Yaman, M., Akin, A., & Kumandas, S. (2025). Genotypic and phenotypic characterization of axonal charcot-marie-tooth disease in cchildhood: Identification of one novel and four known mutations. Genes, 16(8), 917. https://doi.org/10.3390/genes16080917
Ittisoponpisan, S., Islam, S. A., Khanna, T., Alhuzimi, E., David, A., & Sternberg, M. J. E. (2019). Can predicted protein 3D structures provide reliable insights into whether Missense variants are disease Associated? Journal of Molecular Biology, 431(11), 2197-2212. https://doi.org/10.1016/j.jmb.2019.04.009
Kanaan, J., Raj, S., Decourty, L., Saveanu, C., Croquette, V., & Le Hir, H. (2018). UPF1-like helicase grip on nucleic acids dictates processivity. Nature Communications, 9(1), 3752. https://doi.org/10.1038/s41467-018-06313-y
Kulshrestha, R., Forrester, N., Antoniadi, T., Willis, T., Sethuraman, S. K., & Samuels, M. (2018). Charcot marie tooth disease type 2S with late onset diaphragmatic weakness: An atypical case. Neuromuscular Disorders: NMD, 28(12), 1016-1021. https://doi.org/10.1016/j.nmd.2018.09.008
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 Research, 46(D1), D1062-D1067. https://doi.org/10.1093/nar/gkx1153
Lau, A. M., Bordin, N., Kandathil, S. M., Sillitoe, I., Waman, V. P., Wells, J., Orengo, C. A., & Jones, D. T. (2024). Exploring structural diversity across the protein universe with The Encyclopedia of domains. Science, 386(6721), eadq4946. https://doi.org/10.1126/science.adq4946
Lei, L., Zhiqiang, L., Xiaobo, L., Zhengmao, H., Shunxiang, H., Huadong, Z., Beisha, T., & Ruxu, Z. (2022). Clinical and genetic features of charcot-marie-tooth disease patients with IGHMBP2 mutations. Neuromuscular Disorders: NMD, 32(7), 564-571. https://doi.org/10.1016/j.nmd.2022.05.002
Lim, S. C., Bowler, M. W., Lai, T. F., & Song, H. (2012). The IGHMBP2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1. Nucleic Acids Research, 40(21), 11009-11022. https://doi.org/10.1093/nar/gks792
Liu, L., Li, X., Hu, Z., Mao, X., Zi, X., Xia, K., Tang, B., & Zhang, R. (2017). IGHMBP2-related clinical and genetic features in a cohort of Chinese charcot-marie-tooth disease type 2 patients. Neuromuscular Disorders: NMD, 27(2), 193-199. https://doi.org/10.1016/j.nmd.2016.11.008
Liu, L., Zeng, S., Li, X., Xie, Y., Xu, K., Yang, H., Huang, S., Zhao, H., & Zhang, R. (2024). Genotype-phenotype correlations of AR-CMT2S in a cohort of axonal charcot-marie-tooth patients from central south china. Journal of the Peripheral Nervous System, 29(2), 243-251. https://doi.org/10.1111/jns.12633
Montanucci, L., Capriotti, E., Birolo, G., Benevenuta, S., Pancotti, C., Lal, D., & Fariselli, P. (2022). DDGun: An untrained predictor of protein stability changes upon amino acid variants. Nucleic Acids Reserch, 50(W1), W222-W227. https://doi.org/10.1093/nar/gkac325
Ng, P. C., & Henikoff, S. (2003). SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Research, 31(13), 3812-3814. https://doi.org/10.1093/nar/gkg509
Park, J., Desai, H., Liboy-Lugo, J. M., Gu, S., Jowhar, Z., Xu, A., & Floor, S. N. (2024). IGHMBP2 deletion suppresses translation and activates the integrated stress response. Life Science Alliance, 7(8). https://doi.org/10.26508/lsa.202302554
Pedurupillay, C. R., Amundsen, S. S., Baroy, T., Rasmussen, M., Blomhoff, A., Stadheim, B. F., Orstavik, K., Holmgren, A., Iqbal, T., Frengen, E., Misceo, D., & Stromme, P. (2016). Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2. Neuromuscular Disorders, 26(9), 570-575. https://doi.org/10.1016/j.nmd.2016.06.457
Pires, D. E., Ascher, D. B., & Blundell, T. L. (2014). DUET: A server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Research, 42(Web Server issue), W314-319. https://doi.org/10.1093/nar/gku411
Pires, D. E. V., Rodrigues, C. H. M., & Ascher, D. B. (2020). mCSM-membrane: Predicting the effects of mutations on transmembrane proteins. Nucleic Acids Research, 48(W1), W147-W153. https://doi.org/10.1093/nar/gkaa416
Prusty, A. B., Hirmer, A., Sierra-Delgado, J. A., Huber, H., Guenther, U. P., Schlosser, A., Dybkov, O., Yildirim, E., Urlaub, H., Meyer, K. C., Jablonka, S., Erhard, F., & Fischer, U. (2024). RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis. Cell Report, 43(2), 113802. https://doi.org/10.1016/j.celrep.2024.113802
Quang, D., Chen, Y., & Xie, X. (2015). DANN: A deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics, 31(5), 761-763. https://doi.org/10.1093/bioinformatics/btu703
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019). CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Research, 47(D1), D886-D894. https://doi.org/10.1093/nar/gky1016
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., & Committee, A. L. Q. A. (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. Genetics in Medicine, 17(5), 405-424. https://doi.org/10.1038/gim.2015.30
Rodrigues, C. H. M., Pires, D. E. V., & Ascher, D. B. (2021). DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations. Protein Science, 30(1), 60-69. https://doi.org/10.1002/pro.3942
Rzepnikowska, W., Kaminska, J., & Kochanski, A. (2024). The molecular mechanisms that underlie IGHMBP2-related diseases. Neuropathology and Applied Neurobiology, 50(4), e13005. https://doi.org/10.1111/nan.13005
Rzepnikowska, W., & Kochanski, A. (2021). Models for IGHMBP2-associated diseases: An overview and a roadmap for the future. Neuromuscular Disorders, 31(12), 1266-1278. https://doi.org/10.1016/j.nmd.2021.08.001
Savojardo, C., Manfredi, M., Martelli, P. L., & Casadio, R. (2024). DDGemb: Predicting protein stability change upon single and multipoint variations with embeddings and deep learning. Bioinformatics, 41(1). https://doi.org/10.1093/bioinformatics/btaf019
Schottmann, G., Jungbluth, H., Schara, U., Knierim, E., Morales Gonzalez, S., Gill, E., Seifert, F., Norwood, F., Deshpande, C., von Au, K., Schuelke, M., & Senderek, J. (2015). Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy. Neurology, 84(5), 523-531. https://doi.org/10.1212/WNL.0000000000001220
Sievers, F., & Higgins, D. G. (2014). Clustal omega, accurate alignment of very large numbers of sequences. Methods in Molecular Biology, 1079, 105-116. https://doi.org/10.1007/978-1-62703-646-7-6
Tian, Y., Xing, J., Shi, Y., & Yuan, E. (2023). Exploring the relationship between IGHMBP2 gene mutations and spinal muscular atrophy with respiratory distress type 1 and charcot-marie-tooth disease type 2S: a systematic review. Frontiers in Neuroscience, 1252075. https://doi.org/10.3389/fnins.2023.1252075
Tkemaladze, T., Bregvadze, K., Abashishvili, L., Chikvinidze, G., Delgado Vega, A. M., Akbar, F., Khan, S., & Kirmani, S. (2025). Clinical and genetic landscape of IGHMBP2 related disorders: From novel variants to phenotypic insights. American Journal of Medical Genetics, 197(9), e64116. https://doi.org/10.1002/ajmg.a.64116
Tomaselli, P. J., Horga, A., Rossor, A. M., Jaunmuktane, Z., Cortese, A., Blake, J. C., Zarate-Lopez, N., Houlden, H., & Reilly, M. M. (2018). IGHMBP2 mutation associated with organ-specific autonomic dysfunction. Neuromuscular Disorders, 28(12), 1012-1015. https://doi.org/10.1016/j.nmd.2018.08.010
Tran, V. K., Cao, M. H., Nguyen, T. T. H., Le, P. T., Tran, H. A., Vu, D. C., Nguyen, H. T., Nguyen, M. T. P., Bui, T. H., Nguyen, T. B., Ta, T. V., & Tran, T. H. (2024). A novel IGHMBP2 variant and clinical diversity in vietnamese SMARD1 and CMT2S patients. Frontiers in Pediatrics, 12, 1165492. https://doi.org/10.3389/fped.2024.1165492
Wang, K., Li, M., & Hakonarson, H. (2010). ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research, 38(16), e164. https://doi.org/10.1093/nar/gkq603
Worth, C. L., Preissner, R., & Blundell, T. L. (2011). SDM: A server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Research, 39, W215-222. https://doi.org/10.1093/nar/gkr363
Yavas, C., Dogan, M., Ozgor, B., Akbulut, E., & Eroz, R. (2025). Novel biallelic nonsense mutation in IGHMBP2 gene linked to neuropathy (CMT2S): A comprehensive clinical, genetic and bioinformatic analysis of a Turkish patient with literature review. Brain and Development, 47(1), 104313. https://doi.org/10.1016/j.braindev.2024.104313
Yuan, J. H., Hashiguchi, A., Yoshimura, A., Yaguchi, H., Tsuzaki, K., Ikeda, A., Wada-Isoe, K., Ando, M., Nakamura, T., Higuchi, Y., Hiramatsu, Y., Okamoto, Y., & Takashima, H. (2017). Clinical diversity caused by novel IGHMBP2 variants. Journal of Human Genetics, 62(6), 599-604. https://doi.org/10.1038/jhg.2017.15 | ||
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