{"id":13399,"date":"2019-03-13T17:34:34","date_gmt":"2019-03-13T16:34:34","guid":{"rendered":"http:\/\/cyber.pixilie.fr\/?post_type=publications&#038;p=13399"},"modified":"2025-09-11T16:48:04","modified_gmt":"2025-09-11T14:48:04","slug":"mutation-in-human-clpx-elevates-levels-of-%ce%b4-aminolevulinate-synthase-and-protoporphyrin-ix-to-promote-erythropoietic-protoporphyria","status":"publish","type":"publication","link":"https:\/\/cri1149.fr\/en\/publication\/mutation-in-human-clpx-elevates-levels-of-%ce%b4-aminolevulinate-synthase-and-protoporphyrin-ix-to-promote-erythropoietic-protoporphyria\/","title":{"rendered":"Mutation in human CLPX elevates levels of \u03b4-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria."},"content":{"rendered":"","protected":false},"featured_media":0,"template":"","meta":{"_acf_changed":false,"_EventAllDay":false,"_EventTimezone":"","_EventStartDate":"","_EventEndDate":"","_EventStartDateUTC":"","_EventEndDateUTC":"","_EventShowMap":false,"_EventShowMapLink":false,"_EventURL":"","_EventCost":"","_EventCostDescription":"","_EventCurrencySymbol":"","_EventCurrencyCode":"","_EventCurrencyPosition":"","_EventDateTimeSeparator":"","_EventTimeRangeSeparator":"","_EventOrganizerID":[],"_EventVenueID":[],"_OrganizerEmail":"","_OrganizerPhone":"","_OrganizerWebsite":"","_VenueAddress":"","_VenueCity":"","_VenueCountry":"","_VenueProvince":"","_VenueState":"","_VenueZip":"","_VenuePhone":"","_VenueURL":"","_VenueStateProvince":"","_VenueLat":"","_VenueLng":"","_VenueShowMap":false,"_VenueShowMapLink":false},"category_publication":[],"class_list":["post-13399","publication","type-publication","status-publish","hentry"],"acf":{"numero_de_publication":"Proc Natl Acad Sci U S A","date_de_publication":"20170919","numero_doi":"","equipe":[124],"auteurs-liste":[{"texte_libre":true,"auteur-lien":null,"auteur-text":"Yien YY"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Ducamp S"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Van der Vorm LN"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Kardon JR"},{"texte_libre":false,"auteur-lien":13113,"auteur-text":""},{"texte_libre":false,"auteur-lien":13092,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Bergonia HA"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Kafina MD"},{"texte_libre":false,"auteur-lien":13094,"auteur-text":""},{"texte_libre":false,"auteur-lien":13080,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Baker TA"},{"texte_libre":false,"auteur-lien":13142,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Phillips JD"},{"texte_libre":false,"auteur-lien":13128,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Paw BH"}],"auteurs-manuel":"","liens_externes":null,"liens":[{"lien":"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28874591"}],"paragraphe":"<h3 style=\"text-align: justify;\">Abstract<\/h3>\r\n<div class=\"\">\r\n<p style=\"text-align: justify;\">Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the\u00a0<span class=\"highlight\">role<\/span>\u00a0of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of \u03b4-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in\u00a0<i>CLPX<\/i>\u00a0inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism.<\/p>\r\n<\/div>","paragraphe_en":"","documents":null},"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.2 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Mutation in human CLPX elevates levels of \u03b4-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. - CRI<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/cri1149.fr\/publication\/mutation-in-human-clpx-elevates-levels-of-\u03b4-aminolevulinate-synthase-and-protoporphyrin-ix-to-promote-erythropoietic-protoporphyria\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mutation in human CLPX elevates levels of \u03b4-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. - 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