A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes
<p>Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitutio...
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| مؤلفون آخرون: | , , , , , , |
| منشور في: |
2021
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| _version_ | 1864513555905118208 |
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| author | Joanne M. Hildebrand (9407235) |
| author2 | Bernice Lo (3441317) Sara Tomei (3441323) Valentina Mattei (6561395) Samuel N. Young (14152599) Cheree Fitzgibbon (9407253) James M. Murphy (448752) Abeer Fadda (170269) |
| author2_role | author author author author author author author |
| author_facet | Joanne M. Hildebrand (9407235) Bernice Lo (3441317) Sara Tomei (3441323) Valentina Mattei (6561395) Samuel N. Young (14152599) Cheree Fitzgibbon (9407253) James M. Murphy (448752) Abeer Fadda (170269) |
| author_role | author |
| dc.creator.none.fl_str_mv | Joanne M. Hildebrand (9407235) Bernice Lo (3441317) Sara Tomei (3441323) Valentina Mattei (6561395) Samuel N. Young (14152599) Cheree Fitzgibbon (9407253) James M. Murphy (448752) Abeer Fadda (170269) |
| dc.date.none.fl_str_mv | 2021-04-01T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41419-021-03636-5 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/A_family_harboring_an_MLKL_loss_of_function_variant_implicates_impaired_necroptosis_in_diabetes/21598053 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Diabetes Necroptosis |
| dc.title.none.fl_str_mv | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.</p><h2>Other Information</h2> <p> Published in: Cell Death & Disease<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41419-021-03636-5" target="_blank">http://dx.doi.org/10.1038/s41419-021-03636-5</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_bfa836e36e2cb60fc0418e2c247e8ee3 |
| identifier_str_mv | 10.1038/s41419-021-03636-5 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598053 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetesJoanne M. Hildebrand (9407235)Bernice Lo (3441317)Sara Tomei (3441323)Valentina Mattei (6561395)Samuel N. Young (14152599)Cheree Fitzgibbon (9407253)James M. Murphy (448752)Abeer Fadda (170269)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesClinical sciencesMedical biochemistry and metabolomicsDiabetesNecroptosis<p>Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.</p><h2>Other Information</h2> <p> Published in: Cell Death & Disease<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41419-021-03636-5" target="_blank">http://dx.doi.org/10.1038/s41419-021-03636-5</a></p>2021-04-01T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41419-021-03636-5https://figshare.com/articles/journal_contribution/A_family_harboring_an_MLKL_loss_of_function_variant_implicates_impaired_necroptosis_in_diabetes/21598053CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215980532021-04-01T06:00:00Z |
| spellingShingle | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes Joanne M. Hildebrand (9407235) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Diabetes Necroptosis |
| status_str | publishedVersion |
| title | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| title_full | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| title_fullStr | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| title_full_unstemmed | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| title_short | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| title_sort | A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Diabetes Necroptosis |