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Molecular Effects of Mutations in Human Genetic Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 28108

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Special Issue Editors

Dr. Emanuela Leonardi

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1. Department of Woman and Child Health, University of Padua, 35121 Padua, Italy
2. Pediatric Research Institute, Città della Speranza, 35127 Padova, Italy
Interests: neurodevelopmental disorders; Rett syndrome; human genetics; next generation sequencing; mutations; genome interpretation; bioinformatics
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Dr. Giovanni Minervini

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Department of Biomedical Science, University of Padua, 35121 Padua, Italy
Interests: von Hippel-Lindau disease; cancer bioinformatics; computational biology; protein characterization; computational biophysics; molecular dynamic simulations
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Dr. Castrense Savojardo

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Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Interests: bioinformatics and computational biology; protein function prediction; prediction of the impact of variations on protein function and stability

Special Issue Information

Dear Colleagues,

Interpreting the millions of human genetic variants identified by high-throughput sequencing presents one of the greatest scientific challenges of our time. Variants can be classified by their location in genomic DNA, as well as their evolutionary, physico–chemical, structural, and functional properties, and their impact on transcripts, proteins, and molecular interactions. Knowledge of the molecular effects of causal mutations emerges at the interface of human genetics, computational biology, molecular biology, and biophysics. It can provide insights into the pathogenic mechanisms underlying diseases and will help pave the way for mechanism-based drug development strategies.

The aim of this Special Issue is to attract high-quality studies describing computational and experimental approaches for investigating the molecular effects of novel genetic mutations, and providing a useful framework for understanding the molecular defects underlying human diseases. Contributors are also encouraged to submit articles describing use cases, models, and methodological innovations.

The Special Issue will include (1) human genetics studies on genome/exome or targeted sequencing panels that allow either identification of disease–gene associations, characterization of rare diseases with significant genetic heterogeneity, or differential clustering of disease mutations associated with distinct phenotypes; (2) experimental studies investigating how a genetic variant causes disease at the molecular, cellular, and organismal levels; and (3) computational methods devised to predict the impact of genetic variations and their assessment, large-scale statistical studies dissecting key features of disease mutations, or well-curated data repositories of genetic variation and/or disease associations.

Dr. Emanuela LEONARDI

Dr. Giovanni MINERVINI

Dr. Castrense SAVOJARDO
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

variant interpretation
personalized medicine
disease-causing mutations
disease–gene association
molecular mechanisms
pathogenicity prediction
protein stability

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Related Special Issue

Molecular Effects of Mutations in Human Genetic Diseases 2.0 in International Journal of Molecular Sciences (6 articles)

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 191 KiB

Open AccessEditorial

Molecular Effects of Mutations in Human Genetic Diseases

by Emanuela Leonardi, Castrense Savojardo and Giovanni Minervini

Int. J. Mol. Sci. 2022, 23(12), 6408; https://doi.org/10.3390/ijms23126408 - 8 Jun 2022

Viewed by 1233

Abstract

Next-generation sequencing (NGS) has enormously improved the identification of disease-candidate genetic variants [...] Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

Research

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9 pages, 6155 KiB

Open AccessArticle

A Glance into MTHFR Deficiency at a Molecular Level

by Castrense Savojardo, Giulia Babbi, Davide Baldazzi, Pier Luigi Martelli and Rita Casadio

Int. J. Mol. Sci. 2022, 23(1), 167; https://doi.org/10.3390/ijms23010167 - 23 Dec 2021

Cited by 2 | Viewed by 2887

Abstract

MTHFR deficiency still deserves an investigation to associate the phenotype to protein structure variations. To this aim, considering the MTHFR wild type protein structure, with a catalytic and a regulatory domain and taking advantage of state-of-the-art computational tools, we explore the properties of 72 missense variations known to be disease associated. By computing the thermodynamic ΔΔG change according to a consensus method that we recently introduced, we find that 61% of the disease-related variations destabilize the protein, are present both in the catalytic and regulatory domain and correspond to known biochemical deficiencies. The propensity of solvent accessible residues to be involved in protein-protein interaction sites indicates that most of the interacting residues are located in the regulatory domain, and that only three of them, located at the interface of the functional protein homodimer, are both disease-related and destabilizing. Finally, we compute the protein architecture with Hidden Markov Models, one from Pfam for the catalytic domain and the second computed in house for the regulatory domain. We show that patterns of disease-associated, physicochemical variation types, both in the catalytic and regulatory domains, are unique for the MTHFR deficiency when mapped into the protein architecture. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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12 pages, 12812 KiB

Open AccessArticle

Identification of Rare LRP5 Variants in a Cohort of Males with Impaired Bone Mass

by Maria Santa Rocca, Giovanni Minervini, Andrea Di Nisio, Maurizio Merico, Maria Bueno Marinas, Luca De Toni, Kalliopi Pilichou, Andrea Garolla, Carlo Foresta and Alberto Ferlin

Int. J. Mol. Sci. 2021, 22(19), 10834; https://doi.org/10.3390/ijms221910834 - 7 Oct 2021

Cited by 4 | Viewed by 2338

Abstract

Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little attention, thus being underestimated and undertreated. The aim of this study was to identify novel genetic variants in a cohort of 128 males with idiopathic low bone mass using a next-generation sequencing (NGS) panel including genes whose mutations could result in reduced bone mineral density (BMD). Genetic analysis detected in eleven patients ten rare heterozygous variants within the LRP5 gene, which were categorized as VUS (variant of uncertain significance), likely pathogenic and benign variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Protein structural and Bayesian analysis performed on identified LRP5 variants pointed out p.R1036Q and p.R1135C as pathogenic, therefore suggesting the likely association of these two variants with the low bone mass phenotype. In conclusion, this study expands our understanding on the importance of a functional LRP5 protein in bone formation and highlights the necessity to sequence this gene in subjects with idiopathic low BMD. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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18 pages, 4163 KiB

Open AccessArticle

Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

by Farah Kobaisi, Eric Sulpice, Caroline Barette, Nour Fayyad, Marie-Odile Fauvarque, Bassam Badran, Mohammad Fayyad-Kazan, Hussein Fayyad-Kazan, Xavier Gidrol and Walid Rachidi

Int. J. Mol. Sci. 2021, 22(15), 8156; https://doi.org/10.3390/ijms22158156 - 29 Jul 2021

Cited by 4 | Viewed by 2602

Abstract

Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate UVB-induced pyrimidine dimers leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6-4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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10 pages, 2396 KiB

Open AccessCommunication

Chr15q25 Genetic Variant rs16969968 Alters Cell Differentiation in Respiratory Epithelia

by Zania Diabasana, Jeanne-Marie Perotin, Randa Belgacemi, Julien Ancel, Pauline Mulette, Claire Launois, Gonzague Delepine, Xavier Dubernard, Jean-Claude Mérol, Christophe Ruaux, Philippe Gosset, Uwe Maskos, Myriam Polette, Gaëtan Deslée and Valérian Dormoy

Int. J. Mol. Sci. 2021, 22(13), 6657; https://doi.org/10.3390/ijms22136657 - 22 Jun 2021

Cited by 7 | Viewed by 2207

Abstract

The gene cluster region, CHRNA3/CHRNA5/CHRNB4, encoding for nicotinic acetylcholine receptor (nAChR) subunits, contains several genetic variants linked to nicotine addiction and brain disorders. The CHRNA5 single-nucleotide polymorphism (SNP) rs16969968 is strongly associated with nicotine dependence and lung diseases. Using immunostaining studies on tissue sections and air-liquid interface airway epithelial cell cultures, in situ hybridisation, transcriptomic and cytokines detection, we analysed rs16969968 contribution to respiratory airway epithelial remodelling and modulation of inflammation. We provide cellular and molecular analyses which support the genetic association of this polymorphism with impaired ciliogenesis and the altered production of inflammatory mediators. This suggests its role in lung disease development. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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27 pages, 7241 KiB

Open AccessArticle

Signatures of Dermal Fibroblasts from RDEB Pediatric Patients

by Arkadii K. Beilin, Nadezhda A. Evtushenko, Daniil K. Lukyanov, Nikolay N. Murashkin, Eduard T. Ambarchian, Alexander A. Pushkov, Kirill V. Savostyanov, Andrey P. Fisenko, Olga S. Rogovaya, Andrey V. Vasiliev, Ekaterina A. Vorotelyak and Nadya G. Gurskaya

Int. J. Mol. Sci. 2021, 22(4), 1792; https://doi.org/10.3390/ijms22041792 - 11 Feb 2021

Cited by 5 | Viewed by 3503

Abstract

The recessive form of dystrophic epidermolysis bullosa (RDEB) is a debilitating disease caused by impairments in the junctions of the dermis and the basement membrane of the epidermis. Mutations in the COL7A1 gene induce multiple abnormalities, including chronic inflammation and profibrotic changes in the skin. However, the correlations between the specific mutations in COL7A1 and their phenotypic output remain largely unexplored. The mutations in the COL7A1 gene, described here, were found in the DEB register. Among them, two homozygous mutations and two cases of compound heterozygous mutations were identified. We created the panel of primary patient-specific RDEB fibroblast lines (FEB) and compared it with control fibroblasts from healthy donors (FHC). The set of morphological features and the contraction capacity of the cells distinguished FEB from FHC. We also report the relationships between the mutations and several phenotypic traits of the FEB. Based on the analysis of the available RNA-seq data of RDEB fibroblasts, we performed an RT-qPCR gene expression analysis of our cell lines, confirming the differential status of multiple genes while uncovering the new ones. We anticipate that our panels of cell lines will be useful not only for studying RDEB signatures but also for investigating the overall mechanisms involved in disease progression. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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13 pages, 2817 KiB

Open AccessArticle

Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness

by Annemarie Oertli, Susanne Rinné, Robin Moss, Stefan Kääb, Gunnar Seemann, Britt-Maria Beckmann and Niels Decher

Int. J. Mol. Sci. 2021, 22(3), 1112; https://doi.org/10.3390/ijms22031112 - 23 Jan 2021

Cited by 6 | Viewed by 3003

Abstract

KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current I_Ks, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the I_Ks reduction was only observed in homomeric mutants, but not in heteromeric I_Ks channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant I_Ks channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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18 pages, 4052 KiB

Open AccessArticle

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy

by Jorik M. van Rijn, Lael Werner, Yusuf Aydemir, Joey M.A. Spronck, Ben Pode-Shakked, Marliek van Hoesel, Elee Shimshoni, Sylvie Polak-Charcon, Liron Talmi, Makbule Eren, Batia Weiss, Roderick H.J. Houwen, Iris Barshack, Raz Somech, Edward E.S. Nieuwenhuis, Irit Sagi, Annick Raas-Rothschild, Sabine Middendorp and Dror S. Shouval

Int. J. Mol. Sci. 2020, 21(21), 8200; https://doi.org/10.3390/ijms21218200 - 2 Nov 2020

Cited by 4 | Viewed by 3476

Abstract

Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2^KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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Review

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22 pages, 3149 KiB

Open AccessReview

Analysis and Interpretation of the Impact of Missense Variants in Cancer

by Maria Petrosino, Leonore Novak, Alessandra Pasquo, Roberta Chiaraluce, Paola Turina, Emidio Capriotti and Valerio Consalvi

Int. J. Mol. Sci. 2021, 22(11), 5416; https://doi.org/10.3390/ijms22115416 - 21 May 2021

Cited by 37 | Viewed by 5111

Abstract

Large scale genome sequencing allowed the identification of a massive number of genetic variations, whose impact on human health is still unknown. In this review we analyze, by an in silico-based strategy, the impact of missense variants on cancer-related genes, whose effect on protein stability and function was experimentally determined. We collected a set of 164 variants from 11 proteins to analyze the impact of missense mutations at structural and functional levels, and to assess the performance of state-of-the-art methods (FoldX and Meta-SNP) for predicting protein stability change and pathogenicity. The result of our analysis shows that a combination of experimental data on protein stability and in silico pathogenicity predictions allowed the identification of a subset of variants with a high probability of having a deleterious phenotypic effect, as confirmed by the significant enrichment of the subset in variants annotated in the COSMIC database as putative cancer-driving variants. Our analysis suggests that the integration of experimental and computational approaches may contribute to evaluate the risk for complex disorders and develop more effective treatment strategies. Full article

(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases)

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