FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4385891978> ?p ?o ?g. }

• W4385891978 abstract "ABSTRACT Generalised Lymphatic Dysplasia (GLD) is characterised by widespread lymphoedema, with at least one of the following: fetal hydrops, intestinal or pulmonary lymphangiectasia, pleural effusions, pericardial effusions and ascites. Satisfactory medical therapies are lacking. A genetic association has been identified that prevents expression or surface trafficking of PIEZO1, a subunit of mechanically activated calcium-permeable channels. However, PIEZO1 is a large and highly polymorphic gene and interpretation of variants identified in this gene can be challenging. PIEZO1- related GLD with non-immune fetal hydrops is autosomal recessive, however, heterozygous variants in PIEZO1 (often gain-of-function) causing Dehydrated Hereditary Stomatocytosis (DHS) (a relative mild anaemia), may also present with perinatal non-immune hydrops (not caused by anaemia). Here we sought to develop methods to confirm pathogenicity of missense variants of uncertain significance in PIEZO1 , to gain deeper understanding and pharmacological solutions. Four novel GLD-associated missense variants in PIEZO1 are identified that express and surface localise as full-length protein but with reduced or abolished mechanically activated channel function. Yoda1, a small-molecule agonist, functionally rescues the channels and their physiological regulation by mechanical force and hypo-osmolality. The GLD-associated variants mediate intracellular calcium release as well as calcium entry, suggesting two pools of channels and opportunity for increased rescue through access to the intracellular pool. New Yoda1 analogues are also identified that improve rescue. The functional assays have assisted the interpretation of the variants of uncertain significance as the data suggest loss of PIEZO1 force sensing as a cause of the GLD observed in the patients. The potential to pharmacologically overcome the loss of force sensing was demonstrated and supports the concept of stimulation of PIEZO1 with an agonist to address wide-ranging problems of lymphatic insufficiency. GRAPHICAL ABSTRACT HIGHLIGHTS Previously unrecognised variants in PIEZO1 that associate with GLD are identified and characterised and pathogenicity confirmed The variants encode single amino acid changes that inhibit PIEZO1 channel activation by physiological mechanical forces A small-molecule agonist rescues the channels and their physiological regulation Variants are partly intracellular, suggesting an opportunity for improved rescue through the use of intracellular-acting agonists New agonists are identified that improve rescue, suggesting routes to medical therapies for GLD and potentially other disorders of lymphatic insufficiency" @default.
• W4385891978 created "2023-08-18" @default.
• W4385891978 creator A5003481818 @default.
• W4385891978 creator A5003567567 @default.
• W4385891978 creator A5004802161 @default.
• W4385891978 creator A5007042261 @default.
• W4385891978 creator A5012284811 @default.
• W4385891978 creator A5012579486 @default.
• W4385891978 creator A5015556263 @default.
• W4385891978 creator A5024901095 @default.
• W4385891978 creator A5027312074 @default.
• W4385891978 creator A5037455102 @default.
• W4385891978 creator A5037476890 @default.
• W4385891978 creator A5041907537 @default.
• W4385891978 creator A5050288886 @default.
• W4385891978 creator A5064122983 @default.
• W4385891978 creator A5064518084 @default.
• W4385891978 creator A5070809307 @default.
• W4385891978 creator A5079779781 @default.
• W4385891978 creator A5082249954 @default.
• W4385891978 creator A5085024230 @default.
• W4385891978 creator A5088546255 @default.
• W4385891978 creator A5091013451 @default.
• W4385891978 date "2023-08-04" @default.
• W4385891978 modified "2023-09-27" @default.
• W4385891978 title "Small-molecule functional rescue of PIEZO1 channel variants associated with generalised lymphatic dysplasia" @default.
• W4385891978 cites W1591893594 @default.
• W4385891978 cites W1928745964 @default.
• W4385891978 cites W1970413157 @default.
• W4385891978 cites W1983897833 @default.
• W4385891978 cites W1989979419 @default.
• W4385891978 cites W1991643569 @default.
• W4385891978 cites W1999720993 @default.
• W4385891978 cites W2009667219 @default.
• W4385891978 cites W2035330601 @default.
• W4385891978 cites W2043798645 @default.
• W4385891978 cites W2051978340 @default.
• W4385891978 cites W2059145105 @default.
• W4385891978 cites W2063535351 @default.
• W4385891978 cites W2086822491 @default.
• W4385891978 cites W2113018006 @default.
• W4385891978 cites W2115352852 @default.
• W4385891978 cites W2141260882 @default.
• W4385891978 cites W2164004777 @default.
• W4385891978 cites W2173732482 @default.
• W4385891978 cites W2193068214 @default.
• W4385891978 cites W2256087259 @default.
• W4385891978 cites W2542750476 @default.
• W4385891978 cites W2555705980 @default.
• W4385891978 cites W2568168167 @default.
• W4385891978 cites W2605554157 @default.
• W4385891978 cites W2622849565 @default.
• W4385891978 cites W2747918806 @default.
• W4385891978 cites W2760821868 @default.
• W4385891978 cites W2774142732 @default.
• W4385891978 cites W2779962245 @default.
• W4385891978 cites W2783923734 @default.
• W4385891978 cites W2785150634 @default.
• W4385891978 cites W2789612147 @default.
• W4385891978 cites W2792625647 @default.
• W4385891978 cites W2794122131 @default.
• W4385891978 cites W2795448946 @default.
• W4385891978 cites W2886094490 @default.
• W4385891978 cites W2888705553 @default.
• W4385891978 cites W2890154816 @default.
• W4385891978 cites W2890553964 @default.
• W4385891978 cites W2903035331 @default.
• W4385891978 cites W2904736348 @default.
• W4385891978 cites W2905452503 @default.
• W4385891978 cites W2911421449 @default.
• W4385891978 cites W2921245417 @default.
• W4385891978 cites W2979208253 @default.
• W4385891978 cites W3014697035 @default.
• W4385891978 cites W3017074454 @default.
• W4385891978 cites W3029661147 @default.
• W4385891978 cites W3081570112 @default.
• W4385891978 cites W3091960578 @default.
• W4385891978 cites W3111746885 @default.
• W4385891978 cites W3112028900 @default.
• W4385891978 cites W3122704142 @default.
• W4385891978 cites W3129287313 @default.
• W4385891978 cites W3131830629 @default.
• W4385891978 cites W3132100036 @default.
• W4385891978 cites W3196666911 @default.
• W4385891978 cites W3198159306 @default.
• W4385891978 cites W4281742733 @default.
• W4385891978 cites W4282926850 @default.
• W4385891978 cites W4310588821 @default.
• W4385891978 doi "https://doi.org/10.1101/2023.08.01.23292554" @default.
• W4385891978 hasPublicationYear "2023" @default.
• W4385891978 type Work @default.
• W4385891978 citedByCount "0" @default.
• W4385891978 crossrefType "posted-content" @default.
• W4385891978 hasAuthorship W4385891978A5003481818 @default.
• W4385891978 hasAuthorship W4385891978A5003567567 @default.
• W4385891978 hasAuthorship W4385891978A5004802161 @default.
• W4385891978 hasAuthorship W4385891978A5007042261 @default.
• W4385891978 hasAuthorship W4385891978A5012284811 @default.
• W4385891978 hasAuthorship W4385891978A5012579486 @default.
• W4385891978 hasAuthorship W4385891978A5015556263 @default.

• next