Aberrant splicing contributes to severe alpha-spectrin-linked congenital hemolytic anemia

UMMS Affiliation

Department of Pediatrics, Division of Hematology Oncology

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Hematology | Hemic and Immune Systems | Hemic and Lymphatic Diseases | Medical Genetics | Pediatrics


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.


Genetic diseases, Genetics, Hematology

DOI of Published Version



J Clin Invest. 2019 Apr 30;130:2878-2887. doi: 10.1172/JCI127195. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of clinical investigation


Full author list omitted for brevity. For the full list of authors, see article.

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PubMed ID