A novel SPTB mutation causes hereditary spherocytosis via loss-of-function of β-spectrin

Li, Shan; Guo, Ping; Mi, Leyuan; Chai, Xiaojing; Xi, Kewang; Liu, Ting; Li, Lu; Li, Juan

doi:10.1007/s00277-022-04773-3

Cited by 5 publications

(1 citation statement)

References 30 publications

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“…Autosomal dominant (AD) inheritance accounts for 75% of HS cases, mainly through ANK1 , SPTB and SLC4A1 gene variants, whereas autosomal recessive (AR) inheritance is described in approximately 25% of cases, frequently involving SPTA1 and EPB42 gene variants ( Wang et al, 2020 ; Wang D. et al, 2021 ). β-spectrin (encoded by SPTB ) plays a key role in the formation and mechanical stability of the erythrocyte membrane ( He et al, 2018 ; Wang et al, 2020 ; Wang D. et al, 2021 ; Li et al, 2022 ). A total of 206 SPTB variants (mainly localised on exons) are reported in the Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/index.php , accessed 26 March 2021).…”

Section: Introductionmentioning

confidence: 99%

Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis

Xi,

Liu,

Zhu

et al. 2023

Front. Genet.

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Background: Hereditary spherocytosis (HS) is a congenital haemolytic anaemia attributed to dysregulation or abnormal quantities of erythrocyte membrane proteins. Currently, the most common erythrocytic gene, spectrin β (SPTB), variants are located in exons and give rise to mRNA defects. However, the genetic characteristics and pathogenic mechanisms of SPTB intronic variants are not completely understood. This study aimed to analyse a rare intronic inversion variant in the SPTB gene associated with HS, and explore the impact of the variant on SPTB mRNA splicing.Method: The clinical manifestations of the patient were summarised and analysed for spherocytosis phenotype diagnosis. The pathogenic variant was identified in the proband using targeted next-generation and Sanger sequencing. RNA sequencing was performed to analyse whether SPTB gene splicing and expression were affected.Results: Targeted next-generation sequencing identified a novel disease-associated intronic inversion variant of the SPTB gene in the proband. The inversion variant was located between intron 19 and 20, and contained the entire exon 20 and partial sequences of adjacent introns. Sanger sequencing confirmed that the intronic inversion variant only appeared in the genome of the proband, not in his parents. RNA sequencing revealed that the variant could result in the skipping of exon 20 and reduced expression of SPTB mRNA.Conclusion: This study identifies a rare intronic inversion variant in the SPTB gene associated with hereditary spherocytosis. The pathogenic variant can lead to exon 20 skipping and decreased SPTB gene expression. This finding has not been previously reported in any literature. This study can expand the intronic variant spectrum of the SPTB gene, deepen our understanding of HS pathogenesis, and contribute to the genetic diagnosis and clinical management of patients.

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Section: Introductionmentioning

confidence: 99%

Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis

Xi,

Liu,

Zhu

et al. 2023

Front. Genet.

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Hereditary spherocytosis due to a novel variant, p.Q1034X, in the beta subunit of the spectrin gene: A case report

Kugler,

Patel,

Afridi

et al. 2024

Pediatric Hematology Oncology Journal

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Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients

Panarach,

Netsawang,

Nuchprayoon

et al. 2024

Sci Rep

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Hereditary spherocytosis (HS) is the most prevalent form of congenital hemolytic anemia, being caused by genetic mutations in genes encoding red blood cell cytoskeletal proteins. Mutations in the ANK1 and SPTB genes are the most common causes of HS.; however, pathogenicity analyses of these mutations remain limited. This study identified three novel heterozygous mutations in 3 HS patients: c.1994 C > A in ANK1 , c.5692 C > T, and c.3823delG in SPTB by whole-exome sequencing (WES) and validated by Sanger sequencing. To investigate the functional consequences of these mutations, we studied their pathogenicity using in vitro culture erythroblast derived from CD34 + stem cells. All three mutations lead to the generation of a premature stop codon. Real-time PCR assay revealed that the two SPTB mutations resulted in reduced SPTB mRNA expression, suggesting a potential role for the nonsense-mediated mRNA degradation pathway. For the ANK1 mutation, gene expression was not reduced but was predicted to produce a truncated version of the ANK1 protein. Flow cytometry analysis of red blood cell-derived microparticles (MPs) revealed that HS patients had higher MP levels compared to normal subjects. This study contributes to the current understanding of the molecular mechanisms underlying mutations in the ANK1 and SPTB genes in HS. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-78622-w.

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A novel SPTB mutation causes hereditary spherocytosis via loss-of-function of β-spectrin

Cited by 5 publications

References 30 publications

Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis

Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis

Hereditary spherocytosis due to a novel variant, p.Q1034X, in the beta subunit of the spectrin gene: A case report

Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients

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