Abstract
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.
Highlights
The lissencephaly 1 gene, LIS1 (PAFAH1B1), located in chromosome 17p13.3, is one of the major genes associated with neural migration [1,2], a fundamental process of cortex development where postmitotic neurons migrate to their appropriate positions to ensure proper spatial relationships with other cells [3]
We aimed to investigate the significant roles of the targeted genecoded protein with the structural and functional consequence of nsSNPs of LIS1 protein using a wide range of bioinformatics tools and molecular dynamics (MD) simulation
It has been evidenced that a single amino acid alteration in LIS1 protein can cause variable phenotypic manifestations that could result in diverse lissencephaly phenotypes [37]
Summary
The lissencephaly 1 gene, LIS1 (PAFAH1B1), located in chromosome 17p13.3, is one of the major genes associated with neural migration [1,2], a fundamental process of cortex development where postmitotic neurons migrate to their appropriate positions to ensure proper spatial relationships with other cells [3]. LIS1 has been linked to different stages of neuronal development, especially in neuronal migration and neurite outgrowth [8]. Functional information about the LIS1 gene was first disclosed in Aspergillus nidulans regulating microtubules formation and microtubulesbased motors [9]. Sapir et al found that LIS1 interacts with tubulin and modulates microtubule dynamics, indicating a conserved evolutionary function of the LIS1 gene [10]. Overexpression of LIS1 in non-neuronal cells increased retrograde movement of cytoplasmic dynein and promoted the peripheral accumulation of microtubules, reflecting the acquisition of neuron-like dynein behaviors [11]. LIS1 interacts with numerous proteins, including dynein (DYNC1H1) [6], NDEL1 [12], CLIP1 [13], NUDC [14], TUBA1A [15], NAGK [16,17], and doublecortin [18], and promotes essential cellular functions such as cellular transport, proliferation, and migration [19]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
