scholarly journals Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

2020 ◽  
Vol 41 (5) ◽  
pp. 998-1011
Author(s):  
Giulia Ascari ◽  
Frank Peelman ◽  
Pietro Farinelli ◽  
Toon Rosseel ◽  
Nina Lambrechts ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Male Fertility ◽  
Functional Characterization ◽  
Missense Variant ◽  
Founder Allele

scholarly journals Characterization of an N-terminal Nav1.5 channel variant – a potential risk factor for arrhythmias and sudden death?

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Stefanie Scheiper-Welling ◽  
Paolo Zuccolini ◽  
Oliver Rauh ◽  
Britt-Maria Beckmann ◽  
Christof Geisen ◽  
...  
Keyword(s):  
Sudden Death ◽  
Functional Characterization ◽  
Missense Variant ◽  
Hek293 Cells ◽  
Patch Clamp Technique ◽  
Gene Encoding ◽  
Heterozygous Variant ◽  
Cardiac Sodium Channel ◽  
Electrophysiological Measurements

Abstract Background Alterations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance. Methods Mutant as well as wild type GFP tagged Nav1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique. Results Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Nav1.5 current over the entire voltage window. Conclusion The results support the assumption that the detected sequence aberration alters Nav1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.

scholarly journals Comparative functional characterization of novel non-syndromicGJB2gene variant p.Gly45Arg and lethal syndromic variant p.Gly45Glu

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2494 ◽  
Author(s):  
Juan Rodriguez-Paris ◽  
Jörg Waldhaus ◽  
Jeenal A. Gordhandas ◽  
Lynn Pique ◽  
Iris Schrijver
Keyword(s):  
Hearing Loss ◽  
Amino Acid ◽  
Gap Junctions ◽  
Functional Characterization ◽  
Missense Variant ◽  
Amino Acid Position ◽  
Cutaneous Infections ◽  
Transfected Cells ◽  
Novel Variant ◽  
And Function

We characterized a novelGJB2missense variant, c.133G>A, p.Gly45Arg, and compared it with the only other variant at the same amino acid position of the connexin 26 protein (Cx26) reported to date: c.134G>A, p.Gly45Glu. Whereas both variants are associated with hearing loss and are dominantly inherited, p.Gly45Glu has been implicated in the rare fatal keratitis-ichthyosis-deafness (KID) syndrome, which results in cutaneous infections and septicemia with premature demise in the first year of life. In contrast, p.Gly45Arg appears to be non-syndromic. Subcellular localization experiments in transiently co-transfected HeLa cells demonstrated that Cx26-WT (wild-type) and p.Gly45Arg form gap junctions, whereas Cx26-WT with p.Gly45Glu protein does not. The substitution of a nonpolar amino acid glycine in wildtype Cx26 at position 45 with a negatively charged glutamic acid (acidic) has previously been shown to interfere with Ca2+regulation of hemichannel gating and to inhibit the formation of gap junctions, resulting in cell death. The novel variant p.Gly45Arg, however, changes this glycine to a positively charged arginine (basic), resulting in the formation of dysfunctional gap junctions that selectively affect the permeation of negatively charged inositol 1,4,5-trisphosphate (IP3) and contribute to hearing loss. Cx26 p.Gly45Arg transfected cells, unlike cells transfected with p.Gly45Glu, thrived at physiologic Ca2+concentrations, suggesting that Ca2+regulation of hemichannel gating is unaffected in Cx26 p.Gly45Arg transfected cells. Thus, the two oppositely charged amino acids that replace the highly conserved uncharged glycine in p.Gly45Glu and p.Gly45Arg, respectively, produce strikingly different effects on the structure and function of the Cx26 protein.

scholarly journals Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Tahir Zaib ◽  
Chunhui Zhang ◽  
Komal Saleem ◽  
Lidan Xu ◽  
Qian Qin ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Functional Characterization ◽  
Family Members ◽  
Missense Variant ◽  
Chinese Family ◽  
Causative Gene ◽  
Bioinformatic Tools ◽  
Whole Exome

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRCs) inherited in an autosomal-dominant manner. Here, we reported a multigeneration Chinese family clinically diagnosed with LS according to the Amsterdam II criteria. To identify the underlying causative gene for LS in this family, whole-exome sequencing (WES) was performed. A germline missense variant (c.2054C>T:p.S685F) in exon 18 of MLH1 was successfully identified by WES. Sanger sequencing verified the results of WES and also confirmed the cosegregation of the MLH1 missense variant in all affected members of the family including two unaffected family members. Bioinformatic tools predicted the identified MLH1 variant as deleterious. Immunohistochemistry (IHC) staining showed loss of MLH1 and PMS2 protein expression. In vitro expression analysis also revealed that the identified MLH1 missense variant (c.2054C>T:p.S685F) results in reduced expression of both MLH1 and PMS2 proteins. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation c.2054C>T in MLH1 was classified as a “pathogenic” variant. Two unaffected family members were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years as both were at higher risk of LS. In conclusion, our findings widen the genotypic spectrum of MLH1 mutations responsible for LS. This study increases the phenotypic spectrum of LS which will certainly help the clinicians in diagnosing LS in multigeneration families. This study also puts emphasis on the importance of genetic counselling for the benefit of asymptomatic carriers of MMR gene variants who are at higher risk of LS.

Functional characterization of a novel Cx26 (T55N) mutation associated to non-syndromic hearing loss

2005 ◽  
Vol 337 (3) ◽  
pp. 799-805 ◽  
Author(s):  
Salvatore Melchionda ◽  
Massimiliano Bicego ◽  
Elio Marciano ◽  
Annamaria Franzè ◽  
Marcello Morgutti ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Functional Characterization ◽  
Syndromic Hearing Loss

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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