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dc.contributor.authorGallagher, Patrick G.
dc.contributor.authorNewburger, Peter E.
dc.date2022-08-11T08:10:13.000
dc.date.accessioned2022-08-23T16:59:51Z
dc.date.available2022-08-23T16:59:51Z
dc.date.issued2019-04-30
dc.date.submitted2019-05-30
dc.identifier.citation<p>J Clin Invest. 2019 Apr 30;130:2878-2887. doi: 10.1172/JCI127195. <a href="https://doi.org/10.1172/JCI127195">Link to article on publisher's site</a></p>
dc.identifier.issn0021-9738 (Linking)
dc.identifier.doi10.1172/JCI127195
dc.identifier.pmid31038472
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43678
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractThe etiology of severe hemolytic anemia in most patients with recessive hereditary spherocytosis (rHS) and the related disorder hereditary pyropoikilocytosis (HPP) is unknown. Whole exome sequencing of DNA from probands of 24 rHS or HPP kindreds identified numerous mutations in erythrocyte membrane alpha-spectrin (SPTA1). Twenty-eight mutations were novel, with null alleles frequently found in trans to missense mutations. No mutations were identified in a third of SPTA1 alleles (17/48). Whole genome sequencing revealed linkage disequilibrium between the common rHS-linked alpha-spectrinBug Hill polymorphism and a rare intron 30 variant in all 17 mutation-negative alleles. In vitro minigene studies and in vivo splicing analyses revealed the intron 30 variant changes a weak alternate branch point (BP) to a strong BP. This change leads to increased utilization of an alternate 3' splice acceptor site, perturbing normal alpha-spectrin mRNA splicing and creating an elongated mRNA transcript. In vivo mRNA stability studies revealed the newly created termination codon in the elongated transcript activates nonsense mediated decay leading to spectrin deficiency. These results demonstrate a unique mechanism of human genetic disease contributes to the etiology of a third of cases of rHS, facilitating diagnosis and treatment of severe anemia, and identifying a new target for therapeutic manipulation.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31038472&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597203/
dc.subjectGenetic diseases
dc.subjectGenetics
dc.subjectHematology
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetics and Genomics
dc.subjectHematology
dc.subjectHemic and Immune Systems
dc.subjectHemic and Lymphatic Diseases
dc.subjectMedical Genetics
dc.subjectPediatrics
dc.titleAberrant splicing contributes to severe alpha-spectrin-linked congenital hemolytic anemia
dc.typeJournal Article
dc.source.journaltitleThe Journal of clinical investigation
dc.source.volume130
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1252&amp;context=peds_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pp/253
dc.identifier.contextkey14623291
refterms.dateFOA2022-08-23T16:59:51Z
html.description.abstract<p>The etiology of severe hemolytic anemia in most patients with recessive hereditary spherocytosis (rHS) and the related disorder hereditary pyropoikilocytosis (HPP) is unknown. Whole exome sequencing of DNA from probands of 24 rHS or HPP kindreds identified numerous mutations in erythrocyte membrane alpha-spectrin (SPTA1). Twenty-eight mutations were novel, with null alleles frequently found in trans to missense mutations. No mutations were identified in a third of SPTA1 alleles (17/48). Whole genome sequencing revealed linkage disequilibrium between the common rHS-linked alpha-spectrinBug Hill polymorphism and a rare intron 30 variant in all 17 mutation-negative alleles. In vitro minigene studies and in vivo splicing analyses revealed the intron 30 variant changes a weak alternate branch point (BP) to a strong BP. This change leads to increased utilization of an alternate 3' splice acceptor site, perturbing normal alpha-spectrin mRNA splicing and creating an elongated mRNA transcript. In vivo mRNA stability studies revealed the newly created termination codon in the elongated transcript activates nonsense mediated decay leading to spectrin deficiency. These results demonstrate a unique mechanism of human genetic disease contributes to the etiology of a third of cases of rHS, facilitating diagnosis and treatment of severe anemia, and identifying a new target for therapeutic manipulation.</p>
dc.identifier.submissionpathpeds_pp/253
dc.contributor.departmentDepartment of Pediatrics, Division of Hematology Oncology
dc.source.pages2878-2887


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