Phenotypic evolution of UNC80 loss of function

Valkanas, Elise; Schaffer, Katherine; Dunham, Christopher; Maduro, Valerie V.; Souich, Christèle du; Rupps, Rosemarie; Adams, David R.; Baradaran‐Heravi, Alireza; Flynn, Elise; Malicdan, May Christine V.; Gahl, William A.; Toro, Camilo; Boerkoel, Cornelius F.

doi:10.1002/ajmg.a.37929

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…In the last few years, both recessive and dominant human diseases characterized by a range of neurological symptoms including hypotonia, intellectual disability, and seizures, have been shown to be caused by mutations in either NALCN or UNC80 (Al-Sayed et al 2013;Köroglu et al 2013;Aoyagi et al 2015;Chong et al 2015;Bend et al 2016;Fukai et al 2016;Gal et al 2016;Karakaya et al 2016;Lozic et al 2016;Perez et al 2016;Shamseldin et al 2016;Stray-Pedersen et al 2016;Valkanas et al 2016;Wang et al 2016;Vivero et al 2017). Notably, dominant disease-causing mutations in the NALCN channel were modeled in worms and resemble either dominant activated or loss-of-function NCA mutants such as the ones we used in this study (Aoyagi et al 2015;Bend et al 2016).…”

Section: Discussionmentioning

confidence: 99%

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

et al. 2017

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The heterotrimeric G protein G positively regulates neuronal activity and synaptic transmission. Previously, the Rho guanine nucleotide exchange factor Trio was identified as a direct effector of G that acts in parallel to the canonical G effector phospholipase C. Here, we examine how Trio and Rho act to stimulate neuronal activity downstream of G in the nematode Through two forward genetic screens, we identify the cation channels NCA-1 and NCA-2, orthologs of mammalian NALCN, as downstream targets of the G-Rho pathway. By performing genetic epistasis analysis using dominant activating mutations and recessive loss-of-function mutations in the members of this pathway, we show that NCA-1 and NCA-2 act downstream of G in a linear pathway. Through cell-specific rescue experiments, we show that function of these channels in head acetylcholine neurons is sufficient for normal locomotion in Our results suggest that NCA-1 and NCA-2 are physiologically relevant targets of neuronal G-Rho signaling in .

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Section: Discussionmentioning

confidence: 99%

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

et al. 2017

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“…Nevertheless, it would be desirable to test larger datasets on a broader range of rare Mendelian diseases to achieve more accurate and definite insights into Exomiser software performance. Indeed, Exomiser has been already adopted in many sequencing data analysis pipelines to support the identification of Mendelian disease-causing variants [88][89][90][91][92][93][94][95]. Exomiser can also efficiently process whole-genome sequencing samples (in about 5 minutes if only coding data are analyzed and in about 20 minutes for both coding and noncoding data) and is now routinely used in the variant interpretation pipeline of the 100,000 Genomes Project (https://www.genomicsengland.co.uk/) [96].…”

Section: Discussionmentioning

confidence: 99%

An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data

Cipriani

Pontikos

Arno

et al. 2020

Genes

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Next-generation sequencing has revolutionized rare disease diagnostics, but many patients remain without a molecular diagnosis, particularly because many candidate variants usually survive despite strict filtering. Exomiser was launched in 2014 as a Java tool that performs an integrative analysis of patients’ sequencing data and their phenotypes encoded with Human Phenotype Ontology (HPO) terms. It prioritizes variants by leveraging information on variant frequency, predicted pathogenicity, and gene-phenotype associations derived from human diseases, model organisms, and protein–protein interactions. Early published releases of Exomiser were able to prioritize disease-causative variants as top candidates in up to 97% of simulated whole-exomes. The size of the tested real patient datasets published so far are very limited. Here, we present the latest Exomiser version 12.0.1 with many new features. We assessed the performance using a set of 134 whole-exomes from patients with a range of rare retinal diseases and known molecular diagnosis. Using default settings, Exomiser ranked the correct diagnosed variants as the top candidate in 74% of the dataset and top 5 in 94%; not using the patients’ HPO profiles (i.e., variant-only analysis) decreased the performance to 3% and 27%, respectively. In conclusion, Exomiser is an effective support tool for rare Mendelian phenotype-driven variant prioritization.

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“…A tool enabling such analysis is Exome Walker ( 38 ), which is incorporated into Exomiser for exome sequence analysis ( 19 ). This method prioritized mutations in MED23 and UNC80 as likely causes of neurodevelopmental disorders prior to mutations being reported in other families ( 19 , 39 , 40 ).…”

Section: Methodologies and Results Of The Nih Udpmentioning

confidence: 99%

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience

Gall¹,

Valkanas²,

Bello³

et al. 2017

Front. Med.

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Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype–phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

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Phenotypic evolution of UNC80 loss of function

Cited by 18 publications

References 29 publications

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience

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