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17 pages, 4550 KiB

Open AccessArticle

Molecular Modelling Hurdle in the Next-Generation Sequencing Era

by Guerau Fernandez, Dèlia Yubero, Francesc Palau and Judith Armstrong

Int. J. Mol. Sci. 2022, 23(13), 7176; https://doi.org/10.3390/ijms23137176 - 28 Jun 2022

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Abstract

There are challenges in the genetic diagnosis of rare diseases, and pursuing an optimal strategy to identify the cause of the disease is one of the main objectives of any clinical genomics unit. A range of techniques are currently used to characterize the [...] Read more.

There are challenges in the genetic diagnosis of rare diseases, and pursuing an optimal strategy to identify the cause of the disease is one of the main objectives of any clinical genomics unit. A range of techniques are currently used to characterize the genomic variability within the human genome to detect causative variants of specific disorders. With the introduction of next-generation sequencing (NGS) in the clinical setting, geneticists can study single-nucleotide variants (SNVs) throughout the entire exome/genome. In turn, the number of variants to be evaluated per patient has increased significantly, and more information has to be processed and analyzed to determine a proper diagnosis. Roughly 50% of patients with a Mendelian genetic disorder are diagnosed using NGS, but a fair number of patients still suffer a diagnostic odyssey. Due to the inherent diversity of the human population, as more exomes or genomes are sequenced, variants of uncertain significance (VUSs) will increase exponentially. Thus, assigning relevance to a VUS (non-synonymous as well as synonymous) in an undiagnosed patient becomes crucial to assess the proper diagnosis. Multiple algorithms have been used to predict how a specific mutation might affect the protein’s function, but they are far from accurate enough to be conclusive. In this work, we highlight the difficulties of genomic variability determined by NGS that have arisen in diagnosing rare genetic diseases, and how molecular modelling has to be a key component to elucidate the relevance of a specific mutation in the protein’s loss of function or malfunction. We suggest that the creation of a multi-omics data model should improve the classification of pathogenicity for a significant amount of the detected genomic variability. Moreover, we argue how it should be incorporated systematically in the process of variant evaluation to be useful in the clinical setting and the diagnostic pipeline. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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21 pages, 7344 KiB

Open AccessArticle

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function

by Raju Dash, Sarmistha Mitra, Yeasmin Akter Munni, Ho Jin Choi, Md. Chayan Ali, Largess Barua, Tae Jung Jang and Il Soo Moon

Int. J. Mol. Sci. 2021, 22(15), 8048; https://doi.org/10.3390/ijms22158048 - 28 Jul 2021

Cited by 7 | Viewed by 3225

Abstract

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As [...] Read more.

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein–protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein–protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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9 pages, 3901 KiB

Open AccessArticle

Drusenoid Pigment Epithelial Detachment: Genetic and Clinical Characteristics

by Taiyo Shijo, Yoichi Sakurada, Koji Tanaka, Akiko Miki, Seigo Yoneyama, Yumiko Machida, Aya Chubachi, Yu Wakatsuki, Atsushi Sugiyama, Hajime Onoe, Wataru Kikushima, Ryusaburo Mori and Kenji Kashiwagi

Int. J. Mol. Sci. 2021, 22(8), 4074; https://doi.org/10.3390/ijms22084074 - 15 Apr 2021

Cited by 6 | Viewed by 3637

Abstract

Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, [...] Read more.

Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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15 pages, 1680 KiB

Open AccessArticle

Impairments of Photoreceptor Outer Segments Renewal and Phototransduction Due to a Peripherin Rare Haplotype Variant: Insights from Molecular Modeling

by Luigi Donato, Ebtesam Mohamed Abdalla, Concetta Scimone, Simona Alibrandi, Carmela Rinaldi, Karim Mahmoud Nabil, Rosalia D'Angelo and Antonina Sidoti

Int. J. Mol. Sci. 2021, 22(7), 3484; https://doi.org/10.3390/ijms22073484 - 27 Mar 2021

Cited by 28 | Viewed by 2604

Abstract

Background: Retinitis pigmentosa punctata albescens (RPA) is a particular form of retinitis pigmentosa characterized by childhood onset night blindness and areas of peripheral retinal atrophy. We investigated the genetic cause of RPA in a family consisting of two affected Egyptian brothers with healthy [...] Read more.

Background: Retinitis pigmentosa punctata albescens (RPA) is a particular form of retinitis pigmentosa characterized by childhood onset night blindness and areas of peripheral retinal atrophy. We investigated the genetic cause of RPA in a family consisting of two affected Egyptian brothers with healthy consanguineous parents. Methods: Mutational analysis of four RPA causative genes was realized by Sanger sequencing on both probands, and detected variants were subsequently genotyped in their parents. Afterwards, found variants were deeply, statistically, and in silico characterized to determine their possible effects and association with RPA. Results: Both brothers carry three missense PRPH2 variants in a homozygous condition (c.910C > A, c.929G > A, and c.1013A > C) and two promoter variants in RHO (c.-26A > G) and RLBP1 (c.-70G > A) genes, respectively. Haplotype analyses highlighted a PRPH2 rare haplotype variant (GAG), determining a possible alteration of PRPH2 binding with melanoregulin and other outer segment proteins, followed by photoreceptor outer segment instability. Furthermore, an altered balance of transcription factor binding sites, due to the presence of RHO and RLBP1 promoter variants, might determine a comprehensive downregulation of both genes, possibly altering the PRPH2 shared visual-related pathway. Conclusions: Despite several limitations, the study might be a relevant step towards detection of novel scenarios in RPA etiopathogenesis. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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23 pages, 6633 KiB

Open AccessArticle

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter

by Raju Dash, Md. Chayan Ali, Md. Liton Rana, Yeasmin Akter Munni, Largess Barua, Israt Jahan, Mst. Fatema Haque, Md. Abdul Hannan and Il Soo Moon

Int. J. Mol. Sci. 2020, 21(20), 7606; https://doi.org/10.3390/ijms21207606 - 14 Oct 2020

Cited by 28 | Viewed by 6350

Abstract

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when [...] Read more.

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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17 pages, 14810 KiB

Open AccessReview

Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

by Amanda M. Levy, Paulino Gomez-Puertas and Zeynep Tümer

Int. J. Mol. Sci. 2022, 23(8), 4390; https://doi.org/10.3390/ijms23084390 - 15 Apr 2022

Cited by 40 | Viewed by 5620

Abstract

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in [...] Read more.

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in DLG4 encoding PSD-95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD-95 are associated with similar phenotypes, suggesting that deficient PSD-95 may affect the interaction partners, explaining the overlapping symptoms. Here, we review the transmembrane interaction partners of PSD-95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein–protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD-95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD-95, providing clues for therapeutic strategies. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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21 pages, 14802 KiB

Open AccessReview

On the Need to Tell Apart Fraternal Twins eEF1A1 and eEF1A2, and Their Respective Outfits

by Alberto Mills and Federico Gago

Int. J. Mol. Sci. 2021, 22(13), 6973; https://doi.org/10.3390/ijms22136973 - 28 Jun 2021

Cited by 23 | Viewed by 4162

Abstract

eEF1A1 and eEF1A2 are paralogous proteins whose presence in most normal eukaryotic cells is mutually exclusive and developmentally regulated. Often described in the scientific literature under the collective name eEF1A, which stands for eukaryotic elongation factor 1A, their best known activity (in a [...] Read more.

eEF1A1 and eEF1A2 are paralogous proteins whose presence in most normal eukaryotic cells is mutually exclusive and developmentally regulated. Often described in the scientific literature under the collective name eEF1A, which stands for eukaryotic elongation factor 1A, their best known activity (in a monomeric, GTP-bound conformation) is to bind aminoacyl-tRNAs and deliver them to the A-site of the 80S ribosome. However, both eEF1A1 and eEF1A2 are endowed with multitasking abilities (sometimes performed by homo- and heterodimers) and can be located in different subcellular compartments, from the plasma membrane to the nucleus. Given the high sequence identity of these two sister proteins and the large number of post-translational modifications they can undergo, we are often confronted with the dilemma of discerning which is the particular proteoform that is actually responsible for the ascribed biochemical or cellular effects. We argue in this review that acquiring this knowledge is essential to help clarify, in molecular and structural terms, the mechanistic involvement of these two ancestral and abundant G proteins in a variety of fundamental cellular processes other than translation elongation. Of particular importance for this special issue is the fact that several de novo heterozygous missense mutations in the human EEF1A2 gene are associated with a subset of rare but severe neurological syndromes and cardiomyopathies. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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11 pages, 1393 KiB

Open AccessCase Report

Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome

by Pedro A. Lazo, Juan L. García, Paulino Gómez-Puertas, Íñigo Marcos-Alcalde, Cesar Arjona, Alvaro Villarroel, Rogelio González-Sarmiento and Carmen Fons

Int. J. Mol. Sci. 2020, 21(12), 4447; https://doi.org/10.3390/ijms21124447 - 23 Jun 2020

Cited by 5 | Viewed by 3035

Abstract

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe [...] Read more.

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function. Full article

(This article belongs to the Special Issue Macromolecular Modeling to Understand Genetic Disorders)

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