Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases
Purpose Heterozygous dominant-negative (DN) STAT1 variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan. Methods An inborn error of immunity-related gene panel sequencing...
Gespeichert in:
| Veröffentlicht in: | Journal of clinical immunology 2023-02, Vol.43 (2), p.466-478 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 478 |
|---|---|
| container_issue | 2 |
| container_start_page | 466 |
| container_title | Journal of clinical immunology |
| container_volume | 43 |
| creator | Ono, Rintaro Tsumura, Miyuki Shima, Saho Matsuda, Yusuke Gotoh, Kenji Miyata, Yurina Yoto, Yuko Tomomasa, Dan Utsumi, Takanori Ohnishi, Hidenori Kato, Zenichiro Ishiwada, Naruhiko Ishikawa, Aki Wada, Taizo Uhara, Hisashi Nishikomori, Ryuta Hasegawa, Daisuke Okada, Satoshi Kanegane, Hirokazu |
| description | Purpose
Heterozygous dominant-negative (DN)
STAT1
variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan.
Methods
An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells.
Results
Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by
Mycobacterium bovis
bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in
STAT1
, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT
STAT1
.
Conclusion
Four kindred MSMD subjects with 3 novel variants and 1 known variant in
STAT1
were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD. |
| doi_str_mv | 10.1007/s10875-022-01396-1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2888006794</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2888006794</sourcerecordid><originalsourceid>FETCH-LOGICAL-c408t-eefb55fada90ea743dd263c92f3005f570919548704e305360b8ae9a4fa968383</originalsourceid><addsrcrecordid>eNqFkU1v1DAQhi0EokvhD_SALHHhkjL-to9VW2hRC0hduFpOMgGvssk2dkD77-vtFipxgNNInmfe8egh5IjBMQMw7xIDa1QFnFfAhNMVe0IWTBlRceX4U7IAbljlmOQH5EVKKwAQmqvn5EBoIbTRdkFWn8af2NOb5cmS0W9himHIicaBfgybMGBC-iXkiLvHXzH_oJdp7EPGll7j0GJfcHozpwY3Odaxj3lL80ivt81YhyZjievpWUwYEqaX5FkX-oSvHuoh-fr-fHl6UV19_nB5enJVNRJsrhC7WqkutMEBBiNF23ItGsc7AaA6ZcAxp6Q1IFGAEhpqG9AF2QWnrbDikLzd526m8XbGlP06lh_2fblnnJPn1loAbZz8P2qE4MAYdwV98xe6GudpKIcUyjDptNS73XxPNdOY0oSd30xxHaatZ-B30vxemi_S_L00z8rQ64fouV5j-2fkt6UCiD2QSmv4jtPj7n_E3gHuy6Dz</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2771496468</pqid></control><display><type>article</type><title>Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Ono, Rintaro ; Tsumura, Miyuki ; Shima, Saho ; Matsuda, Yusuke ; Gotoh, Kenji ; Miyata, Yurina ; Yoto, Yuko ; Tomomasa, Dan ; Utsumi, Takanori ; Ohnishi, Hidenori ; Kato, Zenichiro ; Ishiwada, Naruhiko ; Ishikawa, Aki ; Wada, Taizo ; Uhara, Hisashi ; Nishikomori, Ryuta ; Hasegawa, Daisuke ; Okada, Satoshi ; Kanegane, Hirokazu</creator><creatorcontrib>Ono, Rintaro ; Tsumura, Miyuki ; Shima, Saho ; Matsuda, Yusuke ; Gotoh, Kenji ; Miyata, Yurina ; Yoto, Yuko ; Tomomasa, Dan ; Utsumi, Takanori ; Ohnishi, Hidenori ; Kato, Zenichiro ; Ishiwada, Naruhiko ; Ishikawa, Aki ; Wada, Taizo ; Uhara, Hisashi ; Nishikomori, Ryuta ; Hasegawa, Daisuke ; Okada, Satoshi ; Kanegane, Hirokazu</creatorcontrib><description>Purpose
Heterozygous dominant-negative (DN)
STAT1
variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan.
Methods
An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells.
Results
Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by
Mycobacterium bovis
bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in
STAT1
, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT
STAT1
.
Conclusion
Four kindred MSMD subjects with 3 novel variants and 1 known variant in
STAT1
were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.</description><identifier>ISSN: 0271-9142</identifier><identifier>EISSN: 1573-2592</identifier><identifier>DOI: 10.1007/s10875-022-01396-1</identifier><identifier>PMID: 36336768</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Abscess ; Abscesses ; Adult ; adulthood ; Anti-Bacterial Agents ; BCG Vaccine ; Biomedical and Life Sciences ; Biomedicine ; blood ; boys ; Child ; Clavicle ; disease course ; DNA ; drainage ; East Asian People ; Female ; genes ; Genetic Predisposition to Disease ; girls ; heterozygosity ; Humans ; Immunology ; Infant ; Infectious Diseases ; Internal Medicine ; Japan ; loss-of-function mutation ; luciferase ; Lung nodules ; lungs ; Lymphadenopathy ; lymphatic diseases ; Male ; Medical Microbiology ; Mutation ; Mycobacterium bovis ; Mycobacterium bovis BCG ; Mycobacterium Infections - diagnosis ; Mycobacterium Infections - genetics ; Original Article ; Osteomyelitis ; Patients ; Spondylitis ; Stat1 protein ; STAT1 Transcription Factor - genetics ; Transfection ; Tuberculosis ; Vaccination ; γ-Interferon</subject><ispartof>Journal of clinical immunology, 2023-02, Vol.43 (2), p.466-478</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-eefb55fada90ea743dd263c92f3005f570919548704e305360b8ae9a4fa968383</citedby><cites>FETCH-LOGICAL-c408t-eefb55fada90ea743dd263c92f3005f570919548704e305360b8ae9a4fa968383</cites><orcidid>0000-0002-8696-9378</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/s10875-022-01396-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10875-022-01396-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36336768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ono, Rintaro</creatorcontrib><creatorcontrib>Tsumura, Miyuki</creatorcontrib><creatorcontrib>Shima, Saho</creatorcontrib><creatorcontrib>Matsuda, Yusuke</creatorcontrib><creatorcontrib>Gotoh, Kenji</creatorcontrib><creatorcontrib>Miyata, Yurina</creatorcontrib><creatorcontrib>Yoto, Yuko</creatorcontrib><creatorcontrib>Tomomasa, Dan</creatorcontrib><creatorcontrib>Utsumi, Takanori</creatorcontrib><creatorcontrib>Ohnishi, Hidenori</creatorcontrib><creatorcontrib>Kato, Zenichiro</creatorcontrib><creatorcontrib>Ishiwada, Naruhiko</creatorcontrib><creatorcontrib>Ishikawa, Aki</creatorcontrib><creatorcontrib>Wada, Taizo</creatorcontrib><creatorcontrib>Uhara, Hisashi</creatorcontrib><creatorcontrib>Nishikomori, Ryuta</creatorcontrib><creatorcontrib>Hasegawa, Daisuke</creatorcontrib><creatorcontrib>Okada, Satoshi</creatorcontrib><creatorcontrib>Kanegane, Hirokazu</creatorcontrib><title>Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases</title><title>Journal of clinical immunology</title><addtitle>J Clin Immunol</addtitle><addtitle>J Clin Immunol</addtitle><description>Purpose
Heterozygous dominant-negative (DN)
STAT1
variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan.
Methods
An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells.
Results
Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by
Mycobacterium bovis
bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in
STAT1
, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT
STAT1
.
Conclusion
Four kindred MSMD subjects with 3 novel variants and 1 known variant in
STAT1
were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.</description><subject>Abscess</subject><subject>Abscesses</subject><subject>Adult</subject><subject>adulthood</subject><subject>Anti-Bacterial Agents</subject><subject>BCG Vaccine</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>blood</subject><subject>boys</subject><subject>Child</subject><subject>Clavicle</subject><subject>disease course</subject><subject>DNA</subject><subject>drainage</subject><subject>East Asian People</subject><subject>Female</subject><subject>genes</subject><subject>Genetic Predisposition to Disease</subject><subject>girls</subject><subject>heterozygosity</subject><subject>Humans</subject><subject>Immunology</subject><subject>Infant</subject><subject>Infectious Diseases</subject><subject>Internal Medicine</subject><subject>Japan</subject><subject>loss-of-function mutation</subject><subject>luciferase</subject><subject>Lung nodules</subject><subject>lungs</subject><subject>Lymphadenopathy</subject><subject>lymphatic diseases</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Mutation</subject><subject>Mycobacterium bovis</subject><subject>Mycobacterium bovis BCG</subject><subject>Mycobacterium Infections - diagnosis</subject><subject>Mycobacterium Infections - genetics</subject><subject>Original Article</subject><subject>Osteomyelitis</subject><subject>Patients</subject><subject>Spondylitis</subject><subject>Stat1 protein</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>Transfection</subject><subject>Tuberculosis</subject><subject>Vaccination</subject><subject>γ-Interferon</subject><issn>0271-9142</issn><issn>1573-2592</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkU1v1DAQhi0EokvhD_SALHHhkjL-to9VW2hRC0hduFpOMgGvssk2dkD77-vtFipxgNNInmfe8egh5IjBMQMw7xIDa1QFnFfAhNMVe0IWTBlRceX4U7IAbljlmOQH5EVKKwAQmqvn5EBoIbTRdkFWn8af2NOb5cmS0W9himHIicaBfgybMGBC-iXkiLvHXzH_oJdp7EPGll7j0GJfcHozpwY3Odaxj3lL80ivt81YhyZjievpWUwYEqaX5FkX-oSvHuoh-fr-fHl6UV19_nB5enJVNRJsrhC7WqkutMEBBiNF23ItGsc7AaA6ZcAxp6Q1IFGAEhpqG9AF2QWnrbDikLzd526m8XbGlP06lh_2fblnnJPn1loAbZz8P2qE4MAYdwV98xe6GudpKIcUyjDptNS73XxPNdOY0oSd30xxHaatZ-B30vxemi_S_L00z8rQ64fouV5j-2fkt6UCiD2QSmv4jtPj7n_E3gHuy6Dz</recordid><startdate>20230201</startdate><enddate>20230201</enddate><creator>Ono, Rintaro</creator><creator>Tsumura, Miyuki</creator><creator>Shima, Saho</creator><creator>Matsuda, Yusuke</creator><creator>Gotoh, Kenji</creator><creator>Miyata, Yurina</creator><creator>Yoto, Yuko</creator><creator>Tomomasa, Dan</creator><creator>Utsumi, Takanori</creator><creator>Ohnishi, Hidenori</creator><creator>Kato, Zenichiro</creator><creator>Ishiwada, Naruhiko</creator><creator>Ishikawa, Aki</creator><creator>Wada, Taizo</creator><creator>Uhara, Hisashi</creator><creator>Nishikomori, Ryuta</creator><creator>Hasegawa, Daisuke</creator><creator>Okada, Satoshi</creator><creator>Kanegane, Hirokazu</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0002-8696-9378</orcidid></search><sort><creationdate>20230201</creationdate><title>Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases</title><author>Ono, Rintaro ; Tsumura, Miyuki ; Shima, Saho ; Matsuda, Yusuke ; Gotoh, Kenji ; Miyata, Yurina ; Yoto, Yuko ; Tomomasa, Dan ; Utsumi, Takanori ; Ohnishi, Hidenori ; Kato, Zenichiro ; Ishiwada, Naruhiko ; Ishikawa, Aki ; Wada, Taizo ; Uhara, Hisashi ; Nishikomori, Ryuta ; Hasegawa, Daisuke ; Okada, Satoshi ; Kanegane, Hirokazu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-eefb55fada90ea743dd263c92f3005f570919548704e305360b8ae9a4fa968383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Abscess</topic><topic>Abscesses</topic><topic>Adult</topic><topic>adulthood</topic><topic>Anti-Bacterial Agents</topic><topic>BCG Vaccine</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>blood</topic><topic>boys</topic><topic>Child</topic><topic>Clavicle</topic><topic>disease course</topic><topic>DNA</topic><topic>drainage</topic><topic>East Asian People</topic><topic>Female</topic><topic>genes</topic><topic>Genetic Predisposition to Disease</topic><topic>girls</topic><topic>heterozygosity</topic><topic>Humans</topic><topic>Immunology</topic><topic>Infant</topic><topic>Infectious Diseases</topic><topic>Internal Medicine</topic><topic>Japan</topic><topic>loss-of-function mutation</topic><topic>luciferase</topic><topic>Lung nodules</topic><topic>lungs</topic><topic>Lymphadenopathy</topic><topic>lymphatic diseases</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Mutation</topic><topic>Mycobacterium bovis</topic><topic>Mycobacterium bovis BCG</topic><topic>Mycobacterium Infections - diagnosis</topic><topic>Mycobacterium Infections - genetics</topic><topic>Original Article</topic><topic>Osteomyelitis</topic><topic>Patients</topic><topic>Spondylitis</topic><topic>Stat1 protein</topic><topic>STAT1 Transcription Factor - genetics</topic><topic>Transfection</topic><topic>Tuberculosis</topic><topic>Vaccination</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ono, Rintaro</creatorcontrib><creatorcontrib>Tsumura, Miyuki</creatorcontrib><creatorcontrib>Shima, Saho</creatorcontrib><creatorcontrib>Matsuda, Yusuke</creatorcontrib><creatorcontrib>Gotoh, Kenji</creatorcontrib><creatorcontrib>Miyata, Yurina</creatorcontrib><creatorcontrib>Yoto, Yuko</creatorcontrib><creatorcontrib>Tomomasa, Dan</creatorcontrib><creatorcontrib>Utsumi, Takanori</creatorcontrib><creatorcontrib>Ohnishi, Hidenori</creatorcontrib><creatorcontrib>Kato, Zenichiro</creatorcontrib><creatorcontrib>Ishiwada, Naruhiko</creatorcontrib><creatorcontrib>Ishikawa, Aki</creatorcontrib><creatorcontrib>Wada, Taizo</creatorcontrib><creatorcontrib>Uhara, Hisashi</creatorcontrib><creatorcontrib>Nishikomori, Ryuta</creatorcontrib><creatorcontrib>Hasegawa, Daisuke</creatorcontrib><creatorcontrib>Okada, Satoshi</creatorcontrib><creatorcontrib>Kanegane, Hirokazu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Journal of clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ono, Rintaro</au><au>Tsumura, Miyuki</au><au>Shima, Saho</au><au>Matsuda, Yusuke</au><au>Gotoh, Kenji</au><au>Miyata, Yurina</au><au>Yoto, Yuko</au><au>Tomomasa, Dan</au><au>Utsumi, Takanori</au><au>Ohnishi, Hidenori</au><au>Kato, Zenichiro</au><au>Ishiwada, Naruhiko</au><au>Ishikawa, Aki</au><au>Wada, Taizo</au><au>Uhara, Hisashi</au><au>Nishikomori, Ryuta</au><au>Hasegawa, Daisuke</au><au>Okada, Satoshi</au><au>Kanegane, Hirokazu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases</atitle><jtitle>Journal of clinical immunology</jtitle><stitle>J Clin Immunol</stitle><addtitle>J Clin Immunol</addtitle><date>2023-02-01</date><risdate>2023</risdate><volume>43</volume><issue>2</issue><spage>466</spage><epage>478</epage><pages>466-478</pages><issn>0271-9142</issn><eissn>1573-2592</eissn><abstract>Purpose
Heterozygous dominant-negative (DN)
STAT1
variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan.
Methods
An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells.
Results
Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by
Mycobacterium bovis
bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in
STAT1
, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT
STAT1
.
Conclusion
Four kindred MSMD subjects with 3 novel variants and 1 known variant in
STAT1
were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>36336768</pmid><doi>10.1007/s10875-022-01396-1</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-8696-9378</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0271-9142 |
| ispartof | Journal of clinical immunology, 2023-02, Vol.43 (2), p.466-478 |
| issn | 0271-9142 1573-2592 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2888006794 |
| source | MEDLINE; SpringerLink Journals |
| subjects | Abscess Abscesses Adult adulthood Anti-Bacterial Agents BCG Vaccine Biomedical and Life Sciences Biomedicine blood boys Child Clavicle disease course DNA drainage East Asian People Female genes Genetic Predisposition to Disease girls heterozygosity Humans Immunology Infant Infectious Diseases Internal Medicine Japan loss-of-function mutation luciferase Lung nodules lungs Lymphadenopathy lymphatic diseases Male Medical Microbiology Mutation Mycobacterium bovis Mycobacterium bovis BCG Mycobacterium Infections - diagnosis Mycobacterium Infections - genetics Original Article Osteomyelitis Patients Spondylitis Stat1 protein STAT1 Transcription Factor - genetics Transfection Tuberculosis Vaccination γ-Interferon |
| title | Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T07%3A21%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Novel%20STAT1%20Variants%20in%20Japanese%20Patients%20with%20Isolated%20Mendelian%20Susceptibility%20to%20Mycobacterial%20Diseases&rft.jtitle=Journal%20of%20clinical%20immunology&rft.au=Ono,%20Rintaro&rft.date=2023-02-01&rft.volume=43&rft.issue=2&rft.spage=466&rft.epage=478&rft.pages=466-478&rft.issn=0271-9142&rft.eissn=1573-2592&rft_id=info:doi/10.1007/s10875-022-01396-1&rft_dat=%3Cproquest_cross%3E2888006794%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2771496468&rft_id=info:pmid/36336768&rfr_iscdi=true |