scholarly journals Mapping OMIM Disease–Related Variations on Protein Domains Reveals an Association Among Variation Type, Pfam Models, and Disease Classes

2021 ◽  
Vol 8 ◽  
Author(s):  
Castrense Savojardo ◽  
Giulia Babbi ◽  
Pier Luigi Martelli ◽  
Rita Casadio
Keyword(s):  
Human Disease ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Mendelian Inheritance ◽  
Protein Coding ◽  
Related Variation ◽  
Diagnosis And Prognosis ◽  
Specific Association ◽  
Physical Features

Human genome resequencing projects provide an unprecedented amount of data about single-nucleotide variations occurring in protein-coding regions and often leading to observable changes in the covalent structure of gene products. For many of these variations, links to Online Mendelian Inheritance in Man (OMIM) genetic diseases are available and are reported in many databases that are collecting human variation data such as Humsavar. However, the current knowledge on the molecular mechanisms that are leading to diseases is, in many cases, still limited. For understanding the complex mechanisms behind disease insurgence, the identification of putative models, when considering the protein structure and chemico-physical features of the variations, can be useful in many contexts, including early diagnosis and prognosis. In this study, we investigate the occurrence and distribution of human disease–related variations in the context of Pfam domains. The aim of this study is the identification and characterization of Pfam domains that are statistically more likely to be associated with disease-related variations. The study takes into consideration 2,513 human protein sequences with 22,763 disease-related variations. We describe patterns of disease-related variation types in biunivocal relation with Pfam domains, which are likely to be possible markers for linking Pfam domains to OMIM diseases. Furthermore, we take advantage of the specific association between disease-related variation types and Pfam domains for clustering diseases according to the Human Disease Ontology, and we establish a relation among variation types, Pfam domains, and disease classes. We find that Pfam models are specific markers of patterns of variation types and that they can serve to bridge genes, diseases, and disease classes. Data are available as Supplementary Material for 1,670 Pfam models, including 22,763 disease-related variations associated to 3,257 OMIM diseases.

scholarly journals Building the vertebrate codex using the gene breaking protein trap library

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Noriko Ichino ◽  
MaKayla R Serres ◽  
Rhianna M Urban ◽  
Mark D Urban ◽  
Anthony J Treichel ◽  
...  
Keyword(s):  
Human Disease ◽  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Transgenic Zebrafish ◽  
Protein Coding ◽  
Coding Regions ◽  
Disease Associated Genes ◽  
Functional Genome Annotation ◽  
Specific Mrna

One key bottleneck in understanding the human genome is the relative under-characterization of 90% of protein coding regions. We report a collection of 1200 transgenic zebrafish strains made with the gene-break transposon (GBT) protein trap to simultaneously report and reversibly knockdown the tagged genes. Protein trap-associated mRFP expression shows previously undocumented expression of 35% and 90% of cloned genes at 2 and 4 days post-fertilization, respectively. Further, investigated alleles regularly show 99% gene-specific mRNA knockdown. Homozygous GBT animals in ryr1b, fras1, tnnt2a, edar and hmcn1 phenocopied established mutants. 204 cloned lines trapped diverse proteins, including 64 orthologs of human disease-associated genes with 40 as potential new disease models. Severely reduced skeletal muscle Ca2+ transients in GBT ryr1b homozygous animals validated the ability to explore molecular mechanisms of genetic diseases. This GBT system facilitates novel functional genome annotation towards understanding cellular and molecular underpinnings of vertebrate biology and human disease.

Molecular Mechanisms of Non-Mendelian Inheritance in Genetic Diseases

1994 ◽  
Vol 4 (1) ◽  
pp. 1-7
Author(s):  
Elena Samilchuk ◽  
Talaat Farag ◽  
Sadika Al-Awadi
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Mendelian Inheritance

scholarly journals Non-Coding RNAs in Pancreatic Cancer Diagnostics and Therapy: Focus on lncRNAs, circRNAs, and piRNAs

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4161
Author(s):  
Yiwei Li ◽  
Mohammed Najeeb Al Hallak ◽  
Philip A. Philip ◽  
Asfar S. Azmi ◽  
Ramzi M. Mohammad
Keyword(s):  
Pancreatic Cancer ◽  
High Mortality ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Cancer Diagnostics ◽  
Circular Rnas ◽  
Diagnosis And Prognosis ◽  
Cellular Signal ◽  
Non Coding Rnas

Pancreatic cancer is an aggressive malignance with high mortality. The lack of early diagnosis and effective therapy contributes to the high mortality of this deadly disease. For a long time being, the alterations in coding RNAs have been considered as major targets for diagnosis and treatment of pancreatic cancer. However, with the advances in high-throughput next generation of sequencing more alterations in non-coding RNAs (ncRNAs) have been discovered in different cancers. Further mechanistic studies have demonstrated that ncRNAs such as long noncoding RNAs (lncRNA), circular RNAs (circRNA) and piwi-interacting RNA (piRNA) play vital roles in the regulation of tumorigenesis, tumor progression and prognosis. In recent years, increasing studies have focused on the roles of ncRNAs in the development and progression of pancreatic cancer. Novel findings have demonstrated that lncRNA, circRNA, and piRNA are critically involved in the regulation of gene expression and cellular signal transduction in pancreatic cancer. In this review, we summarize the current knowledge of roles of lncRNA, circRNA, and piRNA in the diagnosis and prognosis of pancreatic cancer, and molecular mechanisms underlying the regulation of these ncRNAs and related signaling in pancreatic cancer therapy. The information provided here will help to find new strategies for better treatment of pancreatic cancer.

scholarly journals Molecular Crosstalking among Noncoding RNAs: A New Network Layer of Genome Regulation in Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Marco Ragusa ◽  
Cristina Barbagallo ◽  
Duilia Brex ◽  
Angela Caponnetto ◽  
Matilde Cirnigliaro ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Current Knowledge ◽  
Noncoding Rnas ◽  
Special Focus ◽  
Cellular Mechanisms ◽  
Protein Coding ◽  
The Past ◽  
Higher Eukaryotes

Over the past few years, noncoding RNAs (ncRNAs) have been extensively studied because of the significant biological roles that they play in regulation of cellular mechanisms. ncRNAs are associated to higher eukaryotes complexity; accordingly, their dysfunction results in pathological phenotypes, including cancer. To date, most research efforts have been mainly focused on how ncRNAs could modulate the expression of protein-coding genes in pathological phenotypes. However, recent evidence has shown the existence of an unexpected interplay among ncRNAs that strongly influences cancer development and progression. ncRNAs can interact with and regulate each other through various molecular mechanisms generating a complex network including different species of RNAs (e.g., mRNAs, miRNAs, lncRNAs, and circRNAs). Such a hidden network of RNA-RNA competitive interactions pervades and modulates the physiological functioning of canonical protein-coding pathways involved in proliferation, differentiation, and metastasis in cancer. Moreover, the pivotal role of ncRNAs as keystones of network structural integrity makes them very attractive and promising targets for innovative RNA-based therapeutics. In this review we will discuss: (1) the current knowledge on complex crosstalk among ncRNAs, with a special focus on cancer; and (2) the main issues and criticisms concerning ncRNAs targeting in therapeutics.

scholarly journals Long Non-Coding RNAs: The Regulatory Mechanisms, Research Strategies, and Future Directions in Cancers

2020 ◽  
Vol 10 ◽  
Author(s):  
Na Gao ◽  
Yueheng Li ◽  
Jing Li ◽  
Zhengfan Gao ◽  
Zhenzhen Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tumor Development ◽  
Therapeutic Targets ◽  
Regulatory Mechanisms ◽  
Clinical Implementation ◽  
Research Strategies ◽  
Protein Coding ◽  
Functional Studies ◽  
Diagnosis And Prognosis ◽  
Non Coding Rnas

The development and application of whole genome sequencing technology has greatly broadened our horizons on the capabilities of long non-coding RNAs (lncRNAs). LncRNAs are more than 200 nucleotides in length and lack protein-coding potential. Increasing evidence indicates that lncRNAs exert an irreplaceable role in tumor initiation, progression, as well as metastasis, and are novel molecular biomarkers for diagnosis and prognosis of cancer patients. Furthermore, lncRNAs and the pathways they influence might represent promising therapeutic targets for a number of tumors. Here, we discuss the recent advances in understanding of the specific regulatory mechanisms of lncRNAs. We focused on the signal, decoy, guide, and scaffold functions of lncRNAs at the epigenetic, transcription, and post-transcription levels in cancer cells. Additionally, we summarize the research strategies used to investigate the roles of lncRNAs in tumors, including lncRNAs screening, lncRNAs characteristic analyses, functional studies, and molecular mechanisms of lncRNAs. This review will provide a short but comprehensive description of the lncRNA functions in tumor development and progression, thus accelerating the clinical implementation of lncRNAs as tumor biomarkers and therapeutic targets.

scholarly journals Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 88 ◽  
Author(s):  
Katarzyna Piekarowicz ◽  
Magdalena Machowska ◽  
Volha Dzianisava ◽  
Ryszard Rzepecki
Keyword(s):  
Gene Therapy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Subcutaneous Fat ◽  
Current Status ◽  
Single Mutation ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

scholarly journals The Functions and Unique Features of LncRNAs in Cancer Development and Tumorigenesis

2021 ◽  
Vol 22 (2) ◽  
pp. 632
Author(s):  
Kenzui Taniue ◽  
Nobuyoshi Akimitsu
Keyword(s):  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cancer Development ◽  
Biological Functions ◽  
Protein Coding ◽  
Rna Molecules ◽  
The Past ◽  
Cancer Phenotypes ◽  
Coding Potential

Over the past decades, research on cancer biology has focused on the involvement of protein-coding genes in cancer development. Long noncoding RNAs (lncRNAs), which are transcripts longer than 200 nucleotides that lack protein-coding potential, are an important class of RNA molecules that are involved in a variety of biological functions. Although the functions of a majority of lncRNAs have yet to be clarified, some lncRNAs have been shown to be associated with human diseases such as cancer. LncRNAs have been shown to contribute to many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein and RNA. Here we describe the literature regarding the biogenesis and features of lncRNAs. We also present an overview of the current knowledge regarding the roles of lncRNAs in cancer from the view of various aspects of cellular homeostasis, including proliferation, survival, migration and genomic stability. Furthermore, we discuss the methodologies used to identify the function of lncRNAs in cancer development and tumorigenesis. Better understanding of the molecular mechanisms involving lncRNA functions in cancer is critical for the development of diagnostic and therapeutic strategies against tumorigenesis.

scholarly journals Precision Medicine for Continuing Phenotype Expansion of Human Genetic Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Hui Yu ◽  
Victor Wei Zhang
Keyword(s):  
Patient Care ◽  
Precision Medicine ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Diagnostic Purpose ◽  
Disease Spectrum ◽  
Phenotypic Spectrum ◽  
Core Elements ◽  
Common Understanding

Determining the exact genetic causes for a patient and providing definite molecular diagnoses are core elements of precision medicine. Individualized patient care is often limited by our current knowledge of disease etiologies and commonly used phenotypic-based diagnostic approach. The broad and incompletely understood phenotypic spectrum of a disease and various underlying genetic heterogeneity also present extra challenges to our clinical practice. With the rapid adaptation of new sequence technology in clinical setting for diagnostic purpose, phenotypic expansions of disease spectrum are becoming increasingly common. Understanding the underlying molecular mechanisms will help us to integrate genomic information into the workup of individualized patient care and make better clinical decisions.

scholarly journals Sequence of the supernumerary B chromosome of maize provides insight into its drive mechanism and evolution

2021 ◽  
Vol 118 (23) ◽  
pp. e2104254118
Author(s):  
Nicolas Blavet ◽  
Hua Yang ◽  
Handong Su ◽  
Pavel Solanský ◽  
Ryan N. Douglas ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
B Chromosome ◽  
Mendelian Inheritance ◽  
Protein Coding ◽  
Drive Mechanism ◽  
Chromosome Sequence ◽  
Subsequent Degradation ◽  
Preferential Fertilization ◽  
Second Pollen Mitosis ◽  
Insight Into

B chromosomes are enigmatic elements in thousands of plant and animal genomes that persist in populations despite being nonessential. They circumvent the laws of Mendelian inheritance but the molecular mechanisms underlying this behavior remain unknown. Here we present the sequence, annotation, and analysis of the maize B chromosome providing insight into its drive mechanism. The sequence assembly reveals detailed locations of the elements involved with the cis and trans functions of its drive mechanism, consisting of nondisjunction at the second pollen mitosis and preferential fertilization of the egg by the B-containing sperm. We identified 758 protein-coding genes in 125.9 Mb of B chromosome sequence, of which at least 88 are expressed. Our results demonstrate that transposable elements in the B chromosome are shared with the standard A chromosome set but multiple lines of evidence fail to detect a syntenic genic region in the A chromosomes, suggesting a distant origin. The current gene content is a result of continuous transfer from the A chromosomal complement over an extended evolutionary time with subsequent degradation but with selection for maintenance of this nonvital chromosome.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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