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Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia.

Publication ,  Journal Article
Gallagher, PG; Maksimova, Y; Lezon-Geyda, K; Newburger, PE; Medeiros, D; Hanson, RD; Rothman, J; Israels, S; Wall, DA; Sidonio, RF; Sieff, C ...
Published in: J Clin Invest
April 30, 2019

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 α-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 α-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 α-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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 30, 2019

Volume

129

Issue

7

Start / End Page

2878 / 2887

Location

United States

Related Subject Headings

  • Spectrin
  • RNA Splicing
  • RNA Splice Sites
  • Mutation, Missense
  • Male
  • Immunology
  • Humans
  • Female
  • Erythrocyte Membrane
  • Anemia, Hemolytic, Congenital
 

Citation

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Gallagher, P. G., Maksimova, Y., Lezon-Geyda, K., Newburger, P. E., Medeiros, D., Hanson, R. D., … Schulz, V. P. (2019). Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia. J Clin Invest, 129(7), 2878–2887. https://doi.org/10.1172/JCI127195
Gallagher, Patrick G., Yelena Maksimova, Kimberly Lezon-Geyda, Peter E. Newburger, Desiree Medeiros, Robin D. Hanson, Jennifer Rothman, et al. “Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia.J Clin Invest 129, no. 7 (April 30, 2019): 2878–87. https://doi.org/10.1172/JCI127195.
Gallagher PG, Maksimova Y, Lezon-Geyda K, Newburger PE, Medeiros D, Hanson RD, et al. Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia. J Clin Invest. 2019 Apr 30;129(7):2878–87.
Gallagher, Patrick G., et al. “Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia.J Clin Invest, vol. 129, no. 7, Apr. 2019, pp. 2878–87. Pubmed, doi:10.1172/JCI127195.
Gallagher PG, Maksimova Y, Lezon-Geyda K, Newburger PE, Medeiros D, Hanson RD, Rothman J, Israels S, Wall DA, Sidonio RF, Sieff C, Gowans LK, Mittal N, Rivera-Santiago R, Speicher DW, Baserga SJ, Schulz VP. Aberrant splicing contributes to severe α-spectrin-linked congenital hemolytic anemia. J Clin Invest. 2019 Apr 30;129(7):2878–2887.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 30, 2019

Volume

129

Issue

7

Start / End Page

2878 / 2887

Location

United States

Related Subject Headings

  • Spectrin
  • RNA Splicing
  • RNA Splice Sites
  • Mutation, Missense
  • Male
  • Immunology
  • Humans
  • Female
  • Erythrocyte Membrane
  • Anemia, Hemolytic, Congenital