Nuclear Factor-κB Pathway Mediates the Molecular Pathogenesis of LMNA-Related Muscular Dystrophies
LMNA -related muscular dystrophies are caused by mutations of the LMNA gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular me...
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| Veröffentlicht in: | Biochemical genetics 2020-12, Vol.58 (6), p.966-980 |
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| creator | Fan, Yanbin Tan, Dandan Zhang, Xu Song, Danyu Chang, Xingzhi Wang, Shuang Yan, Hui Ge, Lin Yang, Haipo Bönnemann, Carsten Liu, Jingying Wang, Suxia Wu, Xiru Zhang, Hong Xiong, Hui |
| description | LMNA
-related muscular dystrophies are caused by mutations of the
LMNA
gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of
LMNA
-related muscular dystrophies. Muscle specimen of a patient with
LMNA
gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in
LMNA
mutant cells which promoted the expression of downstream inflammatory factors. The
LMNA
mutation also activated the molecular pathway of apoptosis in
LMNA
mutant cells. These are important molecular mechanisms underlying the pathogenesis of
LMNA
-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for
LMNA
-related muscular dystrophies. |
| doi_str_mv | 10.1007/s10528-020-09989-4 |
| format | Article |
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-related muscular dystrophies are caused by mutations of the
LMNA
gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of
LMNA
-related muscular dystrophies. Muscle specimen of a patient with
LMNA
gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in
LMNA
mutant cells which promoted the expression of downstream inflammatory factors. The
LMNA
mutation also activated the molecular pathway of apoptosis in
LMNA
mutant cells. These are important molecular mechanisms underlying the pathogenesis of
LMNA
-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for
LMNA
-related muscular dystrophies.</description><identifier>ISSN: 0006-2928</identifier><identifier>EISSN: 1573-4927</identifier><identifier>DOI: 10.1007/s10528-020-09989-4</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Abnormalities ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cytology ; Gene expression ; Genomic analysis ; Genomic instability ; Human Genetics ; Inflammation ; Mass spectrometry ; Mass spectroscopy ; Medical Microbiology ; Molecular modelling ; Morphology ; Muscles ; Mutants ; Mutation ; NF-κB protein ; Original Article ; Pathogenesis ; Point mutation ; Stability analysis ; Stability augmentation ; Transcription activation ; Ultrastructure ; Zoology</subject><ispartof>Biochemical genetics, 2020-12, Vol.58 (6), p.966-980</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020</rights><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-a8c092c6b774951495cc3f54c7713e44eae6df0497b46676b5ed7824899fcbe83</citedby><cites>FETCH-LOGICAL-c352t-a8c092c6b774951495cc3f54c7713e44eae6df0497b46676b5ed7824899fcbe83</cites><orcidid>0000-0003-4138-2992</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10528-020-09989-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10528-020-09989-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids></links><search><creatorcontrib>Fan, Yanbin</creatorcontrib><creatorcontrib>Tan, Dandan</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Song, Danyu</creatorcontrib><creatorcontrib>Chang, Xingzhi</creatorcontrib><creatorcontrib>Wang, Shuang</creatorcontrib><creatorcontrib>Yan, Hui</creatorcontrib><creatorcontrib>Ge, Lin</creatorcontrib><creatorcontrib>Yang, Haipo</creatorcontrib><creatorcontrib>Bönnemann, Carsten</creatorcontrib><creatorcontrib>Liu, Jingying</creatorcontrib><creatorcontrib>Wang, Suxia</creatorcontrib><creatorcontrib>Wu, Xiru</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Xiong, Hui</creatorcontrib><title>Nuclear Factor-κB Pathway Mediates the Molecular Pathogenesis of LMNA-Related Muscular Dystrophies</title><title>Biochemical genetics</title><addtitle>Biochem Genet</addtitle><description>LMNA
-related muscular dystrophies are caused by mutations of the
LMNA
gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of
LMNA
-related muscular dystrophies. Muscle specimen of a patient with
LMNA
gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in
LMNA
mutant cells which promoted the expression of downstream inflammatory factors. The
LMNA
mutation also activated the molecular pathway of apoptosis in
LMNA
mutant cells. These are important molecular mechanisms underlying the pathogenesis of
LMNA
-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for
LMNA
-related muscular dystrophies.</description><subject>Abnormalities</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cytology</subject><subject>Gene expression</subject><subject>Genomic analysis</subject><subject>Genomic instability</subject><subject>Human Genetics</subject><subject>Inflammation</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Medical Microbiology</subject><subject>Molecular modelling</subject><subject>Morphology</subject><subject>Muscles</subject><subject>Mutants</subject><subject>Mutation</subject><subject>NF-κB protein</subject><subject>Original Article</subject><subject>Pathogenesis</subject><subject>Point mutation</subject><subject>Stability analysis</subject><subject>Stability augmentation</subject><subject>Transcription 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Pathogenesis of LMNA-Related Muscular Dystrophies</title><author>Fan, Yanbin ; Tan, Dandan ; Zhang, Xu ; Song, Danyu ; Chang, Xingzhi ; Wang, Shuang ; Yan, Hui ; Ge, Lin ; Yang, Haipo ; Bönnemann, Carsten ; Liu, Jingying ; Wang, Suxia ; Wu, Xiru ; Zhang, Hong ; Xiong, Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-a8c092c6b774951495cc3f54c7713e44eae6df0497b46676b5ed7824899fcbe83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Abnormalities</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cytology</topic><topic>Gene expression</topic><topic>Genomic analysis</topic><topic>Genomic instability</topic><topic>Human Genetics</topic><topic>Inflammation</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Medical Microbiology</topic><topic>Molecular modelling</topic><topic>Morphology</topic><topic>Muscles</topic><topic>Mutants</topic><topic>Mutation</topic><topic>NF-κB protein</topic><topic>Original Article</topic><topic>Pathogenesis</topic><topic>Point mutation</topic><topic>Stability analysis</topic><topic>Stability augmentation</topic><topic>Transcription activation</topic><topic>Ultrastructure</topic><topic>Zoology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fan, Yanbin</creatorcontrib><creatorcontrib>Tan, Dandan</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Song, Danyu</creatorcontrib><creatorcontrib>Chang, Xingzhi</creatorcontrib><creatorcontrib>Wang, Shuang</creatorcontrib><creatorcontrib>Yan, Hui</creatorcontrib><creatorcontrib>Ge, Lin</creatorcontrib><creatorcontrib>Yang, Haipo</creatorcontrib><creatorcontrib>Bönnemann, Carsten</creatorcontrib><creatorcontrib>Liu, Jingying</creatorcontrib><creatorcontrib>Wang, 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Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear Factor-κB Pathway Mediates the Molecular Pathogenesis of LMNA-Related Muscular Dystrophies</atitle><jtitle>Biochemical genetics</jtitle><stitle>Biochem Genet</stitle><date>2020-12-01</date><risdate>2020</risdate><volume>58</volume><issue>6</issue><spage>966</spage><epage>980</epage><pages>966-980</pages><issn>0006-2928</issn><eissn>1573-4927</eissn><abstract>LMNA
-related muscular dystrophies are caused by mutations of the
LMNA
gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of
LMNA
-related muscular dystrophies. Muscle specimen of a patient with
LMNA
gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in
LMNA
mutant cells which promoted the expression of downstream inflammatory factors. The
LMNA
mutation also activated the molecular pathway of apoptosis in
LMNA
mutant cells. These are important molecular mechanisms underlying the pathogenesis of
LMNA
-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for
LMNA
-related muscular dystrophies.</abstract><cop>New York</cop><pub>Springer US</pub><doi>10.1007/s10528-020-09989-4</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-4138-2992</orcidid></addata></record> |
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| subjects | Abnormalities Apoptosis Biochemistry Biomedical and Life Sciences Biomedicine Cytology Gene expression Genomic analysis Genomic instability Human Genetics Inflammation Mass spectrometry Mass spectroscopy Medical Microbiology Molecular modelling Morphology Muscles Mutants Mutation NF-κB protein Original Article Pathogenesis Point mutation Stability analysis Stability augmentation Transcription activation Ultrastructure Zoology |
| title | Nuclear Factor-κB Pathway Mediates the Molecular Pathogenesis of LMNA-Related Muscular Dystrophies |
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