{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:56:18Z","timestamp":1760151378819,"version":"build-2065373602"},"reference-count":108,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2021R1A2C1008564"],"award-info":[{"award-number":["NRF-2021R1A2C1008564"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Disruptive neuronal migration during early brain development causes severe brain malformation. Characterized by mislocalization of cortical neurons, this condition is a result of the loss of function of migration regulating genes. One known neuronal migration disorder is lissencephaly (LIS), which is caused by deletions or mutations of the LIS1 (PAFAH1B1) gene that has been implicated in regulating the microtubule motor protein cytoplasmic dynein. Although this class of diseases has recently received considerable attention, the roles of non-synonymous polymorphisms (nsSNPs) in LIS1 on lissencephaly progression remain elusive. Therefore, the present study employed combined bioinformatics and molecular modeling approach to identify potential damaging nsSNPs in the LIS1 gene and provide atomic insight into their roles in LIS1 loss of function. Using this approach, we identified three high-risk nsSNPs, including rs121434486 (F31S), rs587784254 (W55R), and rs757993270 (W55L) in the LIS1 gene, which are located on the N-terminal domain of LIS1. Molecular dynamics simulation highlighted that all variants decreased helical conformation, increased the intermonomeric distance, and thus disrupted intermonomeric contacts in the LIS1 dimer. Furthermore, the presence of variants also caused a loss of positive electrostatic potential and reduced dimer binding potential. Since self-dimerization is an essential aspect of LIS1 to recruit interacting partners, thus these variants are associated with the loss of LIS1 functions. As a corollary, these findings may further provide critical insights on the roles of LIS1 variants in brain malformation.<\/jats:p>","DOI":"10.3390\/ijms23063109","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T03:06:10Z","timestamp":1647313570000},"page":"3109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1"],"prefix":"10.3390","volume":"23","author":[{"given":"Ho Jin","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarmistha","family":"Mitra","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-7214","authenticated-orcid":false,"given":"Yeasmin Akter","family":"Munni","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-5308","authenticated-orcid":false,"given":"Raju","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarmin Ummey","family":"Habiba","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md","family":"Sohel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sultana Israt","family":"Jahan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali 3814, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tae Jung","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1608-016X","authenticated-orcid":false,"given":"Il Soo","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/364717a0","article-title":"Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats","volume":"364","author":"Reiner","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/ejhg.2008.213","article-title":"Intragenic deletions and duplications of the LIS1 and DCX genes: A major disease-causing mechanism in lissencephaly and subcortical band heterotopia","volume":"17","author":"Haverfield","year":"2008","journal-title":"Eur. 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