A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait
In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventor...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-03, Vol.113 (11), p.E1536-E1544 |
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| creator | Zhang, Luoying Hirano, Arisa Hsu, Pei-Ken Jones, Christopher R. Sakai, Noriaki Okuro, Masashi McMahon, Thomas Yamazaki, Maya Xu, Ying Saigoh, Noriko Saigoh, Kazumasa Lin, Shu-Ting Kaasik, Krista Nishino, Seiji Ptáček, Louis J. Fu, Ying-Hui |
| description | In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. |
| doi_str_mv | 10.1073/pnas.1600039113 |
| format | Article |
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We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1600039113</identifier><identifier>PMID: 26903630</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Affect - physiology ; Aged ; Amino Acid Sequence ; Animals ; Biological Sciences ; Circadian Clocks - genetics ; Circadian rhythm ; Circadian rhythms ; Emotions ; Female ; Genotype & phenotype ; Humans ; Male ; Mental depression ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Middle Aged ; Molecular Sequence Data ; Period Circadian Proteins - genetics ; Period Circadian Proteins - metabolism ; Photoperiod ; PNAS Plus ; Protein Stability ; Proteins ; Rodents ; Seasonal Affective Disorder - genetics ; Seasonal variations ; Seasons ; Sleep ; Sleep Disorders, Circadian Rhythm - genetics ; Transgenic animals</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-03, Vol.113 (11), p.E1536-E1544</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Mar 15, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-35a05c946c8b071d40ad77dd557594d84a4eba7533dcaf8a770305eeafefe58f3</citedby><cites>FETCH-LOGICAL-c468t-35a05c946c8b071d40ad77dd557594d84a4eba7533dcaf8a770305eeafefe58f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/113/11.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26468720$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26468720$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26903630$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Luoying</creatorcontrib><creatorcontrib>Hirano, Arisa</creatorcontrib><creatorcontrib>Hsu, Pei-Ken</creatorcontrib><creatorcontrib>Jones, Christopher R.</creatorcontrib><creatorcontrib>Sakai, Noriaki</creatorcontrib><creatorcontrib>Okuro, Masashi</creatorcontrib><creatorcontrib>McMahon, Thomas</creatorcontrib><creatorcontrib>Yamazaki, Maya</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Saigoh, Noriko</creatorcontrib><creatorcontrib>Saigoh, Kazumasa</creatorcontrib><creatorcontrib>Lin, Shu-Ting</creatorcontrib><creatorcontrib>Kaasik, Krista</creatorcontrib><creatorcontrib>Nishino, Seiji</creatorcontrib><creatorcontrib>Ptáček, Louis J.</creatorcontrib><creatorcontrib>Fu, Ying-Hui</creatorcontrib><title>A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.</description><subject>Affect - physiology</subject><subject>Aged</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Circadian Clocks - genetics</subject><subject>Circadian rhythm</subject><subject>Circadian rhythms</subject><subject>Emotions</subject><subject>Female</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Male</subject><subject>Mental depression</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Period Circadian Proteins - genetics</subject><subject>Period Circadian Proteins - metabolism</subject><subject>Photoperiod</subject><subject>PNAS Plus</subject><subject>Protein Stability</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Seasonal Affective Disorder - genetics</subject><subject>Seasonal variations</subject><subject>Seasons</subject><subject>Sleep</subject><subject>Sleep Disorders, Circadian Rhythm - genetics</subject><subject>Transgenic animals</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFrGzEQhUVIadyk55xaBDlvMrKk1epSCInbBgIpJT31IMaStpaxVxtJTsm_r4xdNz0Igeab90bzCDlncMlA8atxwHzJWgDgmjF-RCYMNGtaoeGYTACmqunEVJyQdzkvK6VlB2_JybTVwFsOE_Lzmn6bfb97uOX0GVPAoVCLm-wzRWpDsujqGx0XfojlZfQUB0dDLeYcbcDiHf0dyqLC2WOOA67oOkZHS8JQzsibHlfZv9_fp-TH59njzdfm_uHL3c31fWNF25WGSwRptWhtNwfFnAB0SjknpZJauE6g8HNUknNnse9QKeAgvcfe9152PT8ln3a642a-9s76odqvzJjCGtOLiRjM_5UhLMyv-GxEB4wDrwIXe4EUnzY-F7OMm1Q_kw1TSjMtWNtW6mpH2RRzTr4_ODAw2zTMNg3zL43a8fH1YAf-7_orQPfAtvMgx3g9ZsYk37p-2CHLXGJ6JVF3p6bA_wC2dJq0</recordid><startdate>20160315</startdate><enddate>20160315</enddate><creator>Zhang, Luoying</creator><creator>Hirano, Arisa</creator><creator>Hsu, Pei-Ken</creator><creator>Jones, Christopher R.</creator><creator>Sakai, Noriaki</creator><creator>Okuro, Masashi</creator><creator>McMahon, Thomas</creator><creator>Yamazaki, Maya</creator><creator>Xu, Ying</creator><creator>Saigoh, Noriko</creator><creator>Saigoh, Kazumasa</creator><creator>Lin, Shu-Ting</creator><creator>Kaasik, Krista</creator><creator>Nishino, Seiji</creator><creator>Ptáček, Louis J.</creator><creator>Fu, Ying-Hui</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20160315</creationdate><title>A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait</title><author>Zhang, Luoying ; 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We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>26903630</pmid><doi>10.1073/pnas.1600039113</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Affect - physiology Aged Amino Acid Sequence Animals Biological Sciences Circadian Clocks - genetics Circadian rhythm Circadian rhythms Emotions Female Genotype & phenotype Humans Male Mental depression Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Middle Aged Molecular Sequence Data Period Circadian Proteins - genetics Period Circadian Proteins - metabolism Photoperiod PNAS Plus Protein Stability Proteins Rodents Seasonal Affective Disorder - genetics Seasonal variations Seasons Sleep Sleep Disorders, Circadian Rhythm - genetics Transgenic animals |
| title | A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait |
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