Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria
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 pre...
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National Academy of Sciences (U.S.)
2018
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| Online Access: | http://hdl.handle.net/1721.1/114910 https://orcid.org/0000-0002-6621-4461 |
| _version_ | 1826191480232869888 |
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| author | Yien, Yvette Y. Ducamp, Sarah van der Vorm, Lisa N. Manceau, Hana Kannengiesser, Caroline Bergonia, Hector A. Kafina, Martin D. Karim, Zoubida Gouya, Laurent Puy, Hervé Phillips, John D. Nicolas, Gaël Paw, Barry H. Kardon, Julia R. Baker, Tania |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Yien, Yvette Y. Ducamp, Sarah van der Vorm, Lisa N. Manceau, Hana Kannengiesser, Caroline Bergonia, Hector A. Kafina, Martin D. Karim, Zoubida Gouya, Laurent Puy, Hervé Phillips, John D. Nicolas, Gaël Paw, Barry H. Kardon, Julia R. Baker, Tania |
| author_sort | Yien, Yvette Y. |
| collection | MIT |
| description | 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: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPase |
| first_indexed | 2024-09-23T08:56:32Z |
| format | Article |
| id | mit-1721.1/114910 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:56:32Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1149102022-09-30T12:19:28Z Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria Yien, Yvette Y. Ducamp, Sarah van der Vorm, Lisa N. Manceau, Hana Kannengiesser, Caroline Bergonia, Hector A. Kafina, Martin D. Karim, Zoubida Gouya, Laurent Puy, Hervé Phillips, John D. Nicolas, Gaël Paw, Barry H. Kardon, Julia R. Baker, Tania Massachusetts Institute of Technology. Department of Biology Kardon, Julia R. Baker, Tania 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: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPase National Institutes of Health (U.S.) (Grant F32 DK095726) National Institutes of Health (U.S.) (Grant R01 GM049224) 2018-04-24T13:07:05Z 2018-04-24T13:07:05Z 2017-09 2017-05 2018-04-20T14:35:37Z Article http://purl.org/eprint/type/ConferencePaper 0027-8424 1091-6490 http://hdl.handle.net/1721.1/114910 Yien, Yvette Y. et al. “Mutation in humanCLPXelevates Levels ofδ-Aminolevulinate Synthase and Protoporphyrin IX to Promote Erythropoietic Protoporphyria.” Proceedings of the National Academy of Sciences 114, 38 (September 2017): E8045–E8052 © 2017 National Academy of Sciences https://orcid.org/0000-0002-6621-4461 http://dx.doi.org/10.1073/PNAS.1700632114 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences |
| spellingShingle | Yien, Yvette Y. Ducamp, Sarah van der Vorm, Lisa N. Manceau, Hana Kannengiesser, Caroline Bergonia, Hector A. Kafina, Martin D. Karim, Zoubida Gouya, Laurent Puy, Hervé Phillips, John D. Nicolas, Gaël Paw, Barry H. Kardon, Julia R. Baker, Tania Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title | Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title_full | Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title_fullStr | Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title_full_unstemmed | Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title_short | Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria |
| title_sort | mutation in human clpx elevates levels of δ aminolevulinate synthase and protoporphyrin ix to promote erythropoietic protoporphyria |
| url | http://hdl.handle.net/1721.1/114910 https://orcid.org/0000-0002-6621-4461 |
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