scholarly journals A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East

2019 ◽  
Vol 7 ◽  
Author(s):  
Maryam Najafi ◽  
Dor Mohammad Kordi Tamandani ◽  
Anoush Azarfar ◽  
Zeineb Bakey ◽  
Farkhondeh Behjati ◽  
...  
Keyword(s):  
Middle East ◽  
Loss Of Function ◽  
Genomic Deletion ◽  
Mutational Spectrum

scholarly journals The mutational spectrum of holoprosencephaly-associated changes within theSHHgene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis

2009 ◽  
Vol 30 (10) ◽  
pp. E921-E935 ◽  
Author(s):  
Erich Roessler ◽  
Kenia B. El-Jaick ◽  
Christèle Dubourg ◽  
Jorge I. Vélez ◽  
Benjamin D. Solomon ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Structural Alterations ◽  
Mutational Spectrum

scholarly journals The Genomic Landscape of Pediatric Rheumatology Disorders in the Middle East

2020 ◽  
Author(s):  
Basil M Fathalla ◽  
Ali Alsarhan ◽  
Samina Afzal ◽  
Maha EL Naofal ◽  
Ahmad Abou Tayoun
Keyword(s):  
Middle East ◽  
United Arab Emirates ◽  
Diagnostic Yield ◽  
Periodic Fever ◽  
Copy Number Variants ◽  
Loss Of Function ◽  
Management Plans ◽  
Dual Diagnoses ◽  
Positive Rate ◽  
Gene Panels

AbstractGenetic investigations for patients with pediatric rheumatological disorders have been limited to classic genotyping testing, mainly MEFV hotspot mutation analysis, for periodic fever. Therefore, the landscape and clinical utility of comprehensive genomic investigations for a wider range of pediatric rheumatological disorders have not been fully characterized in the Middle East. Here seventy-one pediatric patients, of diverse Arab origins, were clinically and genetically assessed for a spectrum of rheumatology-related disease at the only dedicated tertiary children’s hospital in the United Arab Emirates. Clinical genomic investigations included mainly (76%) next generation sequencing-based gene panels and whole exome sequencing, along with rapid sequencing in the intensive care unit (ICU) and urgent setting. The overall positive yield was 46.5% (16.7%-66.7% for specific indications), while dual diagnoses were made in 2 cases (3%). Although the majority (21/33, 64%) of positive findings involved the MEFV gene, the remaining (12/33, 36%) alterations were attributed to eleven other genes/loci. Copy number variants contributed substantially (5/33, 15.2%) to the overall diagnostic yield. Sequencing-based testing, specifically rapid sequencing, had high positive rate and delivered timely results. Genetic findings guided clinical management plans and interventions in most cases (27/33, 81.8%). We highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers. Our study highlights the importance of comprehensive genomic investigations in patients with pediatric rheumatological disorders, and provides new insights into the pathogenic variation landscape in this group of disorders.

scholarly journals Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome

2021 ◽  
Author(s):  
Sathishkumar Ramaswamy ◽  
Ruchi Jain ◽  
Maha El Naofal ◽  
Nour Halabi ◽  
Alan Taylor ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Middle East ◽  
Human Genome ◽  
Functional Annotation ◽  
Middle Eastern ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Genomic Databases ◽  
Clinical Variant

Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome, and also challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregate whole exome and genome sequencing data from 2,116 individuals in the Middle East and establish the Middle East Variation (MEV) database. Of the high impact coding variants in this database, 34% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing unique Middle Eastern variation which might directly impact clinical variant interpretation. We highlight 167 variants with MAF >1% in the MEV database which were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 365 homozygous loss of function (LoF) variants, the majority of which (239/365, 65.5%) were absent from gnomAD, representing complete knockouts of 229 unique genes in reportedly healthy individuals. Intriguingly, 58 of those genes have several clinically significant variants reported in ClinVar and HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

Errata

2008 ◽  
Vol 13 (2) ◽  
pp. 5-5
Keyword(s):  
Psychotic Disorders ◽  
Pain Syndrome ◽  
Vestibular Disorders ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Neurologic Disorders ◽  
Upper And Lower Extremities ◽  
Impairment Ratings ◽  
Extensive List ◽  
Mental And Behavioral Disorders

Abstract Although most chapters in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, instruct evaluators to perform impairment ratings by first assigning a diagnosis-based class and then assigning a grade within that class, Chapter 13, The Central and Peripheral Nervous System, continues to use a methodology similar to that of the fifth edition. The latter was criticized for duplicating materials that were presented in other chapters and for producing different ratings, so the revision of Chapter 13 attempts to maintain consistency between this chapter and those that address mental and behavioral disorders, loss of function in upper and lower extremities, loss of bowel control, and bladder and sexual function. A table titled Summary of Chapters Used to Rate Various Neurologic Disorders directs physicians to the relevant chapters (ie, instead of Chapter 13) to consult in rating neurologic disorders; the extensive list of conditions that should be addressed in other chapters includes but is not limited to radiculopathy, plexus injuries and other plexopathies, focal neuropathy, complex regional pain syndrome, visual and vestibular disorders, and a range of primary mood, anxiety, and psychotic disorders. The article comments in detail on sections of this chapter, identifies changes in the sixth edition, and provide guidance regarding use of the new edition, resulting in less duplication and greater consistency.

Impairment Tutorial: Rating Facial Disfigurement After an Injury

1998 ◽  
Vol 3 (4) ◽  
pp. 6-6
Author(s):  
Marc T. Taylor
Keyword(s):  
Current Work ◽  
Workers Compensation ◽  
Loss Of Function ◽  
Facial Disfigurement ◽  
Work Related ◽  
Work Related Injury ◽  
Compensation Claim ◽  
Impairment Ratings

Abstract This article discusses two important cases that involve the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides). First, in Vargas v Industrial Com’n of Arizona, a claimant had a pre-existing non–work-related injury to his right knee as well as a work-related injury, and the issue was apportionment of the pre-existing injury. The court held that, under Arizona's statute, the impairment from the pre-existing injury should be subtracted from the current work-related impairment. In the second case, Colorado courts addressed the issue of apportionment in a workers’ compensation claim in which the pre-existing injury was asymptomatic at the time of the work-related injury (Askey v Industrial Claim Appeals Office). In this case, the court held that the worker's benefits should not be reduced to account for an asymptomatic pre-existing condition that could not be rated accurately using the AMA Guides. The AMA Guides bases impairment ratings on anatomic or physiologic loss of function, and if an examinee presents with two or more sequential injuries and calculable impairments, the AMA Guides can be used to apportion between pre-existing and subsequent impairments. Courts often use the AMA Guides to decide statutorily determined benefits and are subject to interpretation by courts and administrative bodies whose interpretations may vary from state to state.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

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