Mutation in human CLPX elevates levels of δ- aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8045-E8052. doi: 10.1073/pnas.1700632114.

Yvette Y Yien ¹, Sarah Ducamp ² ³ ⁴, Lisa N van der Vorm ¹, Julia R Kardon ⁵ ⁶, Hana Manceau ² ³ ⁴, Caroline Kannengiesser ² ⁴ ⁷, Hector A Bergonia ⁸, Martin D Kafina ¹, Zoubida Karim ² ³ ⁴, Laurent Gouya ² ³ ⁴, Tania A Baker ⁹ ⁶, Hervé Puy ¹⁰ ³ ⁴, John D Phillips ¹¹, Gaël Nicolas ² ³ ⁴, Barry H Paw ¹² ¹³ ¹⁴

Affiliations

1 Division of Hematology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115.
2 INSERM U1149, CNRS ERL 8252, Centre de Recherche sur l'inflammation, Université Paris Diderot, Site Bichat, Sorbonne Paris Cité, 75018 Paris, France.
3 Assistance Publique-Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, 92701 Colombes Cedex, France.
4 Laboratory of Excellence, GR-Ex, 75015 Paris, France.
5 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
6 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
7 Département de Génétique, Assistance Publique-Hôpitaux de Paris, HUPNVS, Hôpital Bichat, 75877 Paris Cedex, France.
8 Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT 84112.
9 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; tabaker@mit.edu herve.puy@aphp.fr john.phillips@hsc.utah.edu bpaw@rics.bwh.harvard.edu.
10 INSERM U1149, CNRS ERL 8252, Centre de Recherche sur l'inflammation, Université Paris Diderot, Site Bichat, Sorbonne Paris Cité, 75018 Paris, France; tabaker@mit.edu herve.puy@aphp.fr john.phillips@hsc.utah.edu bpaw@rics.bwh.harvard.edu.
11 Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT 84112; tabaker@mit.edu herve.puy@aphp.fr john.phillips@hsc.utah.edu bpaw@rics.bwh.harvard.edu.
12 Division of Hematology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115; tabaker@mit.edu herve.puy@aphp.fr john.phillips@hsc.utah.edu bpaw@rics.bwh.harvard.edu.
13 Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
14 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.

PMID: 28874591 DOI: 10.1073/pnas.1700632114

Abstract

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 role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-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 CLPX inactivates 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.

Keywords

AAA+ ATPase; ALAS; heme biosynthesis; porphyria; protein unfoldases.

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