Gene-edited pseudogene resurrection corrects p47 phox -deficient chronic granulomatous disease
Pseudogenes are duplicated genes with mutations rendering them nonfunctional. For single-gene disorders with homologous pseudogenes, the pseudogene might be a target for genetic correction. Autosomal-recessive p47 -deficient chronic granulomatous disease (p47-CGD) is a life-threatening immune defici...
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| Veröffentlicht in: | Blood advances 2017-01, Vol.1 (4), p.270 |
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| creator | Merling, Randall K Kuhns, Douglas B Sweeney, Colin L Wu, Xiaolin Burkett, Sandra Chu, Jessica Lee, Janet Koontz, Sherry Di Pasquale, Giovanni Afione, Sandra A Chiorini, John A Kang, Elizabeth M Choi, Uimook De Ravin, Suk See Malech, Harry L |
| description | Pseudogenes are duplicated genes with mutations rendering them nonfunctional. For single-gene disorders with homologous pseudogenes, the pseudogene might be a target for genetic correction. Autosomal-recessive p47
-deficient chronic granulomatous disease (p47-CGD) is a life-threatening immune deficiency caused by mutations in
, a gene with 2 pseudogenes,
and
. The most common
mutation, a GT deletion (ΔGT) at the start of exon 2 (>90% of alleles), is constitutive to
and
.
ΔGT results in premature termination, undetectable protein expression, and defective production of antimicrobial superoxide in neutrophils. We examined strategies for p47-CGD gene correction using engineered zinc-finger nucleases targeting the exon 2 ΔGT in induced pluripotent stem cells or CD34
hematopoietic stem cells derived from p47-CGD patients. Correction of ΔGT in
pseudogenes restores oxidase function in p47-CGD, providing the first demonstration that targeted restoration of pseudogene function can correct a monogenic disorder. |
| format | Article |
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-deficient chronic granulomatous disease (p47-CGD) is a life-threatening immune deficiency caused by mutations in
, a gene with 2 pseudogenes,
and
. The most common
mutation, a GT deletion (ΔGT) at the start of exon 2 (>90% of alleles), is constitutive to
and
.
ΔGT results in premature termination, undetectable protein expression, and defective production of antimicrobial superoxide in neutrophils. We examined strategies for p47-CGD gene correction using engineered zinc-finger nucleases targeting the exon 2 ΔGT in induced pluripotent stem cells or CD34
hematopoietic stem cells derived from p47-CGD patients. Correction of ΔGT in
pseudogenes restores oxidase function in p47-CGD, providing the first demonstration that targeted restoration of pseudogene function can correct a monogenic disorder.</description><identifier>ISSN: 2473-9529</identifier><identifier>PMID: 29296942</identifier><language>eng</language><publisher>United States</publisher><ispartof>Blood advances, 2017-01, Vol.1 (4), p.270</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0001-5874-5775</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29296942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Merling, Randall K</creatorcontrib><creatorcontrib>Kuhns, Douglas B</creatorcontrib><creatorcontrib>Sweeney, Colin L</creatorcontrib><creatorcontrib>Wu, Xiaolin</creatorcontrib><creatorcontrib>Burkett, Sandra</creatorcontrib><creatorcontrib>Chu, Jessica</creatorcontrib><creatorcontrib>Lee, Janet</creatorcontrib><creatorcontrib>Koontz, Sherry</creatorcontrib><creatorcontrib>Di Pasquale, Giovanni</creatorcontrib><creatorcontrib>Afione, Sandra A</creatorcontrib><creatorcontrib>Chiorini, John A</creatorcontrib><creatorcontrib>Kang, Elizabeth M</creatorcontrib><creatorcontrib>Choi, Uimook</creatorcontrib><creatorcontrib>De Ravin, Suk See</creatorcontrib><creatorcontrib>Malech, Harry L</creatorcontrib><title>Gene-edited pseudogene resurrection corrects p47 phox -deficient chronic granulomatous disease</title><title>Blood advances</title><addtitle>Blood Adv</addtitle><description>Pseudogenes are duplicated genes with mutations rendering them nonfunctional. For single-gene disorders with homologous pseudogenes, the pseudogene might be a target for genetic correction. Autosomal-recessive p47
-deficient chronic granulomatous disease (p47-CGD) is a life-threatening immune deficiency caused by mutations in
, a gene with 2 pseudogenes,
and
. The most common
mutation, a GT deletion (ΔGT) at the start of exon 2 (>90% of alleles), is constitutive to
and
.
ΔGT results in premature termination, undetectable protein expression, and defective production of antimicrobial superoxide in neutrophils. We examined strategies for p47-CGD gene correction using engineered zinc-finger nucleases targeting the exon 2 ΔGT in induced pluripotent stem cells or CD34
hematopoietic stem cells derived from p47-CGD patients. Correction of ΔGT in
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-deficient chronic granulomatous disease (p47-CGD) is a life-threatening immune deficiency caused by mutations in
, a gene with 2 pseudogenes,
and
. The most common
mutation, a GT deletion (ΔGT) at the start of exon 2 (>90% of alleles), is constitutive to
and
.
ΔGT results in premature termination, undetectable protein expression, and defective production of antimicrobial superoxide in neutrophils. We examined strategies for p47-CGD gene correction using engineered zinc-finger nucleases targeting the exon 2 ΔGT in induced pluripotent stem cells or CD34
hematopoietic stem cells derived from p47-CGD patients. Correction of ΔGT in
pseudogenes restores oxidase function in p47-CGD, providing the first demonstration that targeted restoration of pseudogene function can correct a monogenic disorder.</abstract><cop>United States</cop><pmid>29296942</pmid><orcidid>https://orcid.org/0000-0001-5874-5775</orcidid></addata></record> |
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| ispartof | Blood advances, 2017-01, Vol.1 (4), p.270 |
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| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| title | Gene-edited pseudogene resurrection corrects p47 phox -deficient chronic granulomatous disease |
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