{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T20:15:15Z","timestamp":1767989715102,"version":"3.49.0"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019345","name":"King Salman Center for Disability Research","doi-asserted-by":"publisher","award":["KSRG-2023-242"],"award-info":[{"award-number":["KSRG-2023-242"]}],"id":[{"id":"10.13039\/501100019345","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a chronic, inherited neurodegenerative condition marked by chorea, dementia, and changes in personality. The primary cause of HD is a mutation characterized by the expansion of a triplet repeat (CAG) within the huntingtin gene located on chromosome 4. Despite substantial progress in elucidating the molecular and cellular mechanisms of HD, an effective treatment for this disorder is not available so far. In recent years, researchers have been interested in studying cerebrospinal fluid (CSF) as a source of biomarkers that could aid in the diagnosis and therapeutic development of this disorder. Immunoglobulin heavy constant gamma 1 (IGHG1) is one of the CSF proteins found to increase significantly in HD. Considering this, it is reasonable to study the potential involvement of deleterious mutations in IGHG1 in the pathogenesis of this disorder. In this study, we explored the potential impact of deleterious mutations on IGHG1 and their subsequent association with HD. We evaluated 126 single-point amino acid substitutions for their impact on the structure and functionality of the IGHG1 protein while exploiting multiple computational resources such as SIFT, PolyPhen-2, FATHMM, SNPs&amp;Go mCSM, DynaMut2, MAESTROweb, PremPS, MutPred2, and PhD-SNP. The sequence- and structure-based tools highlighted 10 amino acid substitutions that were deleterious and destabilizing. Subsequently, out of these 10 mutations, eight variants (Y32C, Y32D, P34S, V39E, C83R, C83Y, V85M, and H87Q) were identified as pathogenic by disease phenotype predictors. Finally, two pathogenic variants (Y32C and P34S) were found to reduce the solubility of the protein, suggesting their propensity to form protein aggregates. These variants also exhibited higher residual frustration within the protein structure. Considering these findings, the study hypothesized that the identified variants of IGHG1 may compromise its function and potentially contribute to HD pathogenesis.<\/jats:p>","DOI":"10.3390\/jpm14040380","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T05:44:36Z","timestamp":1711950276000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Elucidating the Impact of Deleterious Mutations on IGHG1 and Their Association with Huntington\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Alaa","family":"Shafie","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4579-2921","authenticated-orcid":false,"given":"Amal Adnan","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Anjum","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-7056","authenticated-orcid":false,"given":"Anas","family":"Shamsi","sequence":"additional","affiliation":[{"name":"Center of Medical and Bio-Allied Health Sciences Research (CMBHSR), Ajman University, Ajman P.O. Box 346, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-4940","authenticated-orcid":false,"given":"Md. Imtaiyaz","family":"Hassan","sequence":"additional","affiliation":[{"name":"Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","article-title":"Huntington\u2019s disease","volume":"369","author":"Walker","year":"2007","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ncl.2014.09.003","article-title":"Huntington disease: Pathogenesis and treatment","volume":"33","author":"Dayalu","year":"2015","journal-title":"Neurol. 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