Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency
Diamond‐Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythr...
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| Veröffentlicht in: | Pathology international 2021-12, Vol.71 (12), p.803-813 |
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| creator | Fukui, Yuko Hayano, Satoru Kawanabe, Noriaki Wang, Ziyi Shimada, Akira Saito, Megumu K. Asaka, Isao Kamioka, Hiroshi |
| description | Diamond‐Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro‐apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53‐mediated apoptosis in chondrocytes. Murine double minute 2 (MDM2), the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53‐mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients. |
| doi_str_mv | 10.1111/pin.13168 |
| format | Article |
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Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro‐apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53‐mediated apoptosis in chondrocytes. Murine double minute 2 (MDM2), the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53‐mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients.</description><identifier>ISSN: 1320-5463</identifier><identifier>EISSN: 1440-1827</identifier><identifier>DOI: 10.1111/pin.13168</identifier><identifier>PMID: 34587661</identifier><language>eng</language><publisher>Australia: Wiley Subscription Services, Inc</publisher><subject>Abnormalities ; Anemia ; Anemia, Diamond-Blackfan - genetics ; Anemia, Diamond-Blackfan - pathology ; Animals ; Aplasia ; Apoptosis ; Apoptosis - genetics ; Bax protein ; Biomedical materials ; Cell differentiation ; Child ; chondrocyte ; Chondrocytes ; Chondrocytes - pathology ; cleft lip and palate ; Diamonds ; Diamond‐Blackfan anemia ; Evolution ; Genes ; Genetic disorders ; Genetic Markers ; Haploinsufficiency ; Humans ; Induced Pluripotent Stem Cells ; iPS cell ; Male ; MDM2 protein ; Mice ; Mucin ; Mucins ; Mutation ; Osteogenesis ; Osteogenesis - genetics ; p53 Protein ; Phosphorylation ; Pluripotency ; Progenitor cells ; Ribosomal proteins ; Ribosomal Proteins - genetics ; RPL5 ; Stem cell transplantation ; Stem cells</subject><ispartof>Pathology international, 2021-12, Vol.71 (12), p.803-813</ispartof><rights>2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd</rights><rights>2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4878-5fda7896c17460194a03e34d3cbdd5b5fd9f3620a0b6e65109fdfa04b0d105c73</citedby><cites>FETCH-LOGICAL-c4878-5fda7896c17460194a03e34d3cbdd5b5fd9f3620a0b6e65109fdfa04b0d105c73</cites><orcidid>0000-0002-4166-9531</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fpin.13168$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fpin.13168$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34587661$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fukui, Yuko</creatorcontrib><creatorcontrib>Hayano, Satoru</creatorcontrib><creatorcontrib>Kawanabe, Noriaki</creatorcontrib><creatorcontrib>Wang, Ziyi</creatorcontrib><creatorcontrib>Shimada, Akira</creatorcontrib><creatorcontrib>Saito, Megumu K.</creatorcontrib><creatorcontrib>Asaka, Isao</creatorcontrib><creatorcontrib>Kamioka, Hiroshi</creatorcontrib><title>Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency</title><title>Pathology international</title><addtitle>Pathol Int</addtitle><description>Diamond‐Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro‐apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53‐mediated apoptosis in chondrocytes. Murine double minute 2 (MDM2), the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53‐mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients.</description><subject>Abnormalities</subject><subject>Anemia</subject><subject>Anemia, Diamond-Blackfan - genetics</subject><subject>Anemia, Diamond-Blackfan - pathology</subject><subject>Animals</subject><subject>Aplasia</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Bax protein</subject><subject>Biomedical materials</subject><subject>Cell differentiation</subject><subject>Child</subject><subject>chondrocyte</subject><subject>Chondrocytes</subject><subject>Chondrocytes - pathology</subject><subject>cleft lip and palate</subject><subject>Diamonds</subject><subject>Diamond‐Blackfan anemia</subject><subject>Evolution</subject><subject>Genes</subject><subject>Genetic disorders</subject><subject>Genetic Markers</subject><subject>Haploinsufficiency</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells</subject><subject>iPS cell</subject><subject>Male</subject><subject>MDM2 protein</subject><subject>Mice</subject><subject>Mucin</subject><subject>Mucins</subject><subject>Mutation</subject><subject>Osteogenesis</subject><subject>Osteogenesis - genetics</subject><subject>p53 Protein</subject><subject>Phosphorylation</subject><subject>Pluripotency</subject><subject>Progenitor cells</subject><subject>Ribosomal proteins</subject><subject>Ribosomal Proteins - genetics</subject><subject>RPL5</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><issn>1320-5463</issn><issn>1440-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kb9uFDEQhy1EREKg4AWQJRpSbOL_6yshBHLSCSIEteX12jkHr72xd4m2o6biGXkSnFxIgcQ0M9J8-jSjHwAvMDrGtU5GH48xxUI-AgeYMdRgSdrHdaYENZwJug-elnKFEG6pQE_APmVctkLgA_BzHb_bMvlLPfkUYXJw2lo4pGDNHHSGRs_FFjjH3uaw-HgJx-1SvNEB6i6mPOjgJ18JH-E7r4cU-98_fr0N2nxzOkId7eA1HKvdxqnAGz9t4eeLDYdbPYbkY5md86YuzfIM7Dkdin1-3w_B1_dnX07Pm82nD-vTN5vGMNnKhrtet3IlDG6ZQHjFNKKWsp6aru95V9crRwVBGnXCCo7RyvVOI9ahHiNuWnoIXu-8Y07Xc31eDb4YG0I9Ns1FEd5KzCkht-irf9CrNOdYr1NEYCSJoERW6mhHmZxKydapMftB50VhpG4DUjUgdRdQZV_eG-dusP0D-TeRCpzsgBsf7PJ_k7pYf9wp_wAbTp1o</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Fukui, Yuko</creator><creator>Hayano, Satoru</creator><creator>Kawanabe, Noriaki</creator><creator>Wang, Ziyi</creator><creator>Shimada, Akira</creator><creator>Saito, Megumu K.</creator><creator>Asaka, Isao</creator><creator>Kamioka, Hiroshi</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4166-9531</orcidid></search><sort><creationdate>202112</creationdate><title>Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency</title><author>Fukui, Yuko ; Hayano, Satoru ; Kawanabe, Noriaki ; Wang, Ziyi ; Shimada, Akira ; Saito, Megumu K. ; Asaka, Isao ; Kamioka, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4878-5fda7896c17460194a03e34d3cbdd5b5fd9f3620a0b6e65109fdfa04b0d105c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Abnormalities</topic><topic>Anemia</topic><topic>Anemia, Diamond-Blackfan - genetics</topic><topic>Anemia, Diamond-Blackfan - pathology</topic><topic>Animals</topic><topic>Aplasia</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Bax protein</topic><topic>Biomedical materials</topic><topic>Cell differentiation</topic><topic>Child</topic><topic>chondrocyte</topic><topic>Chondrocytes</topic><topic>Chondrocytes - pathology</topic><topic>cleft lip and palate</topic><topic>Diamonds</topic><topic>Diamond‐Blackfan anemia</topic><topic>Evolution</topic><topic>Genes</topic><topic>Genetic disorders</topic><topic>Genetic Markers</topic><topic>Haploinsufficiency</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells</topic><topic>iPS cell</topic><topic>Male</topic><topic>MDM2 protein</topic><topic>Mice</topic><topic>Mucin</topic><topic>Mucins</topic><topic>Mutation</topic><topic>Osteogenesis</topic><topic>Osteogenesis - genetics</topic><topic>p53 Protein</topic><topic>Phosphorylation</topic><topic>Pluripotency</topic><topic>Progenitor cells</topic><topic>Ribosomal proteins</topic><topic>Ribosomal Proteins - genetics</topic><topic>RPL5</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fukui, Yuko</creatorcontrib><creatorcontrib>Hayano, Satoru</creatorcontrib><creatorcontrib>Kawanabe, Noriaki</creatorcontrib><creatorcontrib>Wang, Ziyi</creatorcontrib><creatorcontrib>Shimada, Akira</creatorcontrib><creatorcontrib>Saito, Megumu K.</creatorcontrib><creatorcontrib>Asaka, Isao</creatorcontrib><creatorcontrib>Kamioka, Hiroshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Pathology international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fukui, Yuko</au><au>Hayano, Satoru</au><au>Kawanabe, Noriaki</au><au>Wang, Ziyi</au><au>Shimada, Akira</au><au>Saito, Megumu K.</au><au>Asaka, Isao</au><au>Kamioka, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency</atitle><jtitle>Pathology international</jtitle><addtitle>Pathol Int</addtitle><date>2021-12</date><risdate>2021</risdate><volume>71</volume><issue>12</issue><spage>803</spage><epage>813</epage><pages>803-813</pages><issn>1320-5463</issn><eissn>1440-1827</eissn><abstract>Diamond‐Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53‐mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro‐apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53‐mediated apoptosis in chondrocytes. Murine double minute 2 (MDM2), the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53‐mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients.</abstract><cop>Australia</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34587661</pmid><doi>10.1111/pin.13168</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-4166-9531</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Abnormalities Anemia Anemia, Diamond-Blackfan - genetics Anemia, Diamond-Blackfan - pathology Animals Aplasia Apoptosis Apoptosis - genetics Bax protein Biomedical materials Cell differentiation Child chondrocyte Chondrocytes Chondrocytes - pathology cleft lip and palate Diamonds Diamond‐Blackfan anemia Evolution Genes Genetic disorders Genetic Markers Haploinsufficiency Humans Induced Pluripotent Stem Cells iPS cell Male MDM2 protein Mice Mucin Mucins Mutation Osteogenesis Osteogenesis - genetics p53 Protein Phosphorylation Pluripotency Progenitor cells Ribosomal proteins Ribosomal Proteins - genetics RPL5 Stem cell transplantation Stem cells |
| title | Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency |
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