Disruption of protein function by pathogenic mutations: common and uncommon mechanisms

2019 ◽  
Vol 97 (1) ◽  
pp. 46-57 ◽  
Author(s):  
Mikko Taipale
Keyword(s):  
Protein Function ◽  
Loss Of Function ◽  
Protein Coding ◽  
Cellular Processes ◽  
Coding Regions ◽  
Mendelian Disorders ◽  
Pathogenic Variants ◽  
Disease Mutations ◽  
Protein Folding Pathways ◽  
Almost All

Mutations in protein-coding regions underlie almost all Mendelian disorders, drive tumorigenesis, and contribute to susceptibility to common diseases. Despite the great diversity of diseases that are caused by coding mutations, the cellular processes that affect, and are affected by, pathogenic variants at the molecular level are fundamentally conserved. Experimental and computational approaches have revealed that a substantial fraction of disease mutations are not simple loss-of-function alleles. Rather, these pathogenic variants disrupt protein function in more subtle ways by tuning protein folding pathways, altering subcellular trafficking, interrupting signaling cascades, and rewiring highly connected interaction networks. Focusing mainly on Mendelian disorders, this review discusses the common mechanisms by which deleterious mutations disrupt protein function and how these disruptions can be exploited in the development of novel therapies.

scholarly journals LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Qian Li ◽  
Chengbin Lei ◽  
Changliang Lu ◽  
Jingye Wang ◽  
Min Gao ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Transcriptional Activation ◽  
Digestive System ◽  
Malignant Tumors ◽  
Loss Of Function ◽  
Protein Coding ◽  
Cellular Processes ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Pancreatic adenocarcinoma (PAAD), one of the most prevailing malignant tumors in digestive system, is identified as one of the main culprits of cancer-associated mortality. Despite long intergenic non-protein coding RNA 1232 (LINC01232) is found to be upregulated in TCGA PAAD tissues and associated with poor prognosis, the potential of LINC01232 in PAAD progression still needs more explorations. In this study, LINC01232 was chosen to be the research object in PAAD cellular processes. Functionally, loss-of function assays were carried out and the experimental results indicated that suppression of LINC01232 hindered the deterioration of PAAD by affecting cell proliferation and migration. Furthermore, relationship between LINC01232 and its nearby gene transmembrane 9 superfamily member 2 (TM9SF2) was investigated. The same expression pattern of TM9SF2 in TCGA PAAD samples was observed. It was found that upregulation of LINC01232 could be a crucial factor for the dysregulation of TM9SF2. Mechanistically, LINC01232 recruited EIF4A3 to boost TM9SF2 mRNA stability. Besides, our findings demonstrated that the transcriptional activation of LINC01232 and TM9SF2 was mediated by SP1. Therefore, we concluded that LINC01232 executed carcinogenic properties in PAAD progression via regulation of TM9SF2. In conclusion, this study was the first to unveil the role and molecular mechanism of LINC01232, suggesting LINC01232 as a promising molecular target for pancreatic cancer treatment.

The nature and development of cancer: Cancer mutations and their implications

2020 ◽  
pp. 445-455
Author(s):  
James D. Brenton ◽  
Tim Eisen
Keyword(s):  
Protein Function ◽  
Chromosomal Rearrangements ◽  
Regulation Of Gene Expression ◽  
Tumour Suppressor Genes ◽  
Cancer Type ◽  
Loss Of Function ◽  
Physiological Control ◽  
Cellular Processes ◽  
Cancer Mutations ◽  
The Individual

Cancer is a genetic disease in which progressive accumulation of mutations in the genome of somatic cells induces abnormal biological capabilities. Cancer-inducing mutations may originate from single base substitutions or large chromosomal rearrangements; but ultimately they disrupt normal cellular processes by altering protein function or disturbing the regulation of gene expression. Loss-of-function mutations in tumour suppressor genes inactivate physiological control of cell processes, whereas gain-of-function mutations directly affect physiological networks and, for example, induce pathological activation of signalling pathways. For many common cancers, we are now close to defining unique sets of somatic alterations which confer a specific signature of the cancer type and are also highly specific to the individual patient.

scholarly journals OR22-05 Rare Biallelic Variants in Obesity-Related Genes in the Madrid Pediatric Obesity Cohort

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Gabriel Á Martos-Moreno ◽  
Ida Hatoum Moeller ◽  
Álvaro Martín-Rivada ◽  
Luis A Pérez-Jurado ◽  
Jesús Argente
Keyword(s):  
Childhood Obesity ◽  
Severe Obesity ◽  
Genetic Disorders ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Protein Coding ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Biallelic Mutations

Abstract BACKGROUND: Obesity is a heterogenous disease resulting from environmental and genetic factors and is characterized by disordered energy balance, regulated in part by the hypothalamic melanocortin-4 receptor (MC4R), including neuronal ciliary assembly and trafficking pathways.1 Rare loss-of-function variants in genes encoding components of this pathway are associated with severe obesity and hyperphagia, with or without additional features.2 However, such rare genetic disorders may be underestimated due to a lack of genetic screening in individuals with severe obesity.3 Our objective was to identify and characterize rare genetic variants in a Spanish population from Madrid with childhood obesity. Methods: This analysis was conducted from a prospectively-collected cohort of children with obesity, generally with a BMI>+3DS. Participants were sequenced for 35 obesity-related genes, including 23 genes related to Bardet-Biedl (BBS) and Alström syndromes, plus an additional 12 genes associated with non-syndromic, monogenic causes of obesity, to identify individuals with rare (<1% frequency in gnomAD) potentially biallelic (homozygous and compound heterozygous) non-synonymous variants in protein-coding regions. Results: Of the 1019 Spanish patients with obesity, 493 (48.4%) were female and the mean age and BMI were 10.41 ± 3.38 years and 4.38 ± 1.76 SDS (79.8% above +3 SDS), respectively. We identified 26 rare potentially biallelic variants in 25 unique individuals, including 2 individuals with homozygous variants in POMC, 3 individuals with two variants in SRC1, one individual with two variants in ADCY3, and one individual with a homozygous mutation in LEP. In addition, we identified 18 individuals with biallelic mutations in one of 23 BBS or ALMS1 genes, including two individuals with known pathogenic variants and clinically confirmed BBS. Conclusions: Rare and potentially biallelic sequence variants were identified in 25 individuals with childhood obesity. These results support the use of genetic testing for individuals with severe obesity who may be candidates for specific clinical interventions or additional targeted therapies.

scholarly journals Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ashraf Yahia ◽  
Liena E. O. Elsayed ◽  
Remi Valter ◽  
Ahlam A. A. Hamed ◽  
Inaam N. Mohammed ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Neurological Phenotype ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Generation Sequencing

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity.Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

scholarly journals Ranking of non-coding pathogenic variants and putative essential regions of the human genome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alex Wells ◽  
David Heckerman ◽  
Ali Torkamani ◽  
Li Yin ◽  
Jonathan Sebat ◽  
...  
Keyword(s):  
Genome Organization ◽  
Regulatory Elements ◽  
Structural Features ◽  
Loss Of Function ◽  
3D Genome ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Machine Learning Model ◽  
Using Data

AbstractA gene is considered essential if loss of function results in loss of viability, fitness or in disease. This concept is well established for coding genes; however, non-coding regions are thought less likely to be determinants of critical functions. Here we train a machine learning model using functional, mutational and structural features, including new genome essentiality metrics, 3D genome organization and enhancer reporter data to identify deleterious variants in non-coding regions. We assess the model for functional correlates by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements in over 3 Mb of genome sequence. Finally, we explore two user cases that involve indels and the disruption of enhancers associated with a developmental disease. We rank variants in the non-coding genome according to their predicted deleteriousness. The model prioritizes non-coding regions associated with regulation of important genes and with cell viability, an in vitro surrogate of essentiality.

scholarly journals The Role of Deubiquitinases in Oncovirus and Host Interactions

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yueshuo Li ◽  
Feng Shi ◽  
Jianmin Hu ◽  
Longlong Xie ◽  
Ann M. Bode ◽  
...  
Keyword(s):  
Life Cycle ◽  
Signaling Pathways ◽  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Antiviral Signaling ◽  
Host Interactions ◽  
Cellular Processes ◽  
Ubiquitin System ◽  
Almost All

Infection-related cancer comprises one-sixth of the global cancer burden. Oncoviruses can directly or indirectly contribute to tumorigenesis. Ubiquitination is a dynamic and reversible posttranslational modification that participates in almost all cellular processes. Hijacking of the ubiquitin system by viruses continues to emerge as a central theme around the viral life cycle. Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling pathways, as well as acting as key mediators between the virus and its host. In this review, we focus on the multiple functions of DUBs in RIG-I-like receptors (RLRs) and stimulator of interferon genes (STING)-mediated antiviral signaling pathways, oncoviruses regulation of NF-κB activation, oncoviral life cycle, and the potential of DUB inhibitors as therapeutic strategies.

scholarly journals Towards a systematic map of the functional role of protein phosphorylation

2019 ◽  
Author(s):  
Cristina Viéitez ◽  
Bede P. Busby ◽  
David Ochoa ◽  
André Mateus ◽  
Marco Galardini ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Systematic Map ◽  
Gene Deletions ◽  
Chemical Genetic ◽  
Cellular Processes ◽  
Growth Profiles ◽  
Functional Relevance ◽  
Almost All

AbstractPhosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phosphomutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.

scholarly journals Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

2019 ◽  
Vol 5 (2) ◽  
pp. e565 ◽  
Author(s):  
Chong Sun ◽  
Jie Song ◽  
Yanjun Jiang ◽  
Chongbo Zhao ◽  
Jiahong Lu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Protein Function ◽  
Trna Synthetase ◽  
Insertion Mutation ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Charcot Marie Tooth Disease ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

scholarly journals G-quadruplex-forming sequences as potential drivers of genetic diversity in primate protein coding genes

2020 ◽  
Author(s):  
Manuel Jara-Espejo ◽  
Sergio Roberto Peres Line
Keyword(s):  
Genetic Diversity ◽  
Amino Acid ◽  
Protein Function ◽  
Evolutionary Dynamics ◽  
Regulatory Elements ◽  
Evolutionary Trend ◽  
Protein Coding ◽  
Coding Regions ◽  
Mutational Pattern ◽  
Species Specific

ABSTRACTWhile non-coding G-quadruplexes (G4s) act as conserved regulatory elements when located in gene promoter and splice sites, the G4 evolutionary conservation in protein coding regions have been low explored. To address the evolutionary dynamics acting on coding G4, we mapped and characterized potential G4-forming sequences across twenty-four primate’s gene orthologous. We found that potentially more stable G4 motifs exist in coding regions following a species-specific trend. Moreover, these motifs depicted the least conserved sites across primates at both the DNA and amino acid levels and are characterized by an indel-rich mutational pattern. This trend was not observed for less stable G4 motifs. A deeper analysis revealed that [G>=3N1]4 motifs, depicting potentially most stable G4s, were associated with the lowest conservation and highest indel frequencies. This mutational pattern was more evident when G4-associated amino acid regions were analyzed. We discuss the possibility of an overall conservation of less/moderate stability G4, while more stable G4 may be preserved or arises in a species-specific manner, which may explain their low conservation. Since structure-prone motifs, including G4, have the potential to induce genomic instability, this evolutionary trend may contribute to avoid broad deleterious effects driven by stable G4 on protein function while promoting genetic diversity across close-related species.

scholarly journals FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

2020 ◽  
Vol 21 (14) ◽  
pp. 5112 ◽  
Author(s):  
Daniela Tavian ◽  
Sara Missaglia ◽  
Sandro Michelini ◽  
Paolo Enrico Maltese ◽  
Elena Manara ◽  
...  
Keyword(s):  
Protein Function ◽  
Clinical Findings ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Mutant Proteins ◽  
Transactivation Activity ◽  
Forkhead Box ◽  
Disease Mutations ◽  
Stop Mutation

FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death.

Sign in / Sign up

Export Citation Format

Share Document