Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

Bogusławska, Dżamila M.; Skulski, Michał; Machnicka, Beata; Potoczek, S; Kraszewski, Sebastian; Kuliczkowski, Kazimierz; Sikorski, Aleksander F.

doi:10.3390/ijms222011007

Cited by 5 publications

(9 citation statements)

References 49 publications

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“…This study indicated that the most frequently affected genes in Turkish children with HS were ANK1and SPTB. This result is similar to previous results found in American, European and Chinese populations (19)(20)(21). All mutations are novel and unique, having not previously been reported in a different population.…”

Section: Discussionsupporting

confidence: 92%

Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience

Kocaaga

ÇAKMAK

2022

Batı Karadeniz Tıp Dergisi

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Aim: Hereditary spherocytosis (HS) is a prevalent cause of congenital hemolytic anemia in Northern Europeans. It is characterized by spherocytes resulting from defects in the erythrocyte structural membrane proteins spectrin and ankyrin. To date, more than five candidate genes, including ANK1, SPTB, SPTA1, SLC4A1, and EPB42 have been linked to HS. Here, we aim to investigate the presence of novel as well as known mutations in eight Turkish children with clinically suspected HS. Material and Methods: We presented the clinical features of the patients and identified the causative gene variants using targeted exome sequencing. Eight children who were clinically suspected of having HS enrolled in this study. A family and medical history, clinical examination, relevant laboratory test results, osmotic fragility test (OFT), and genetic results were evaluated. Results: Six causative variants, including three ANK1 variants, two SPTB variants and one SLC4A1 variant were detected. All these mutations were novel variants. ANK1 and SPTB are the most common mutant genes in children with HS. Conclusion: This study expanded the mutation spectrum of ANK1, SPTB and SLC4A1. This is the first study to determine the genetic and clinical characteristics of children with HS in Turkey.

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Section: Discussionsupporting

confidence: 92%

Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience

Kocaaga

ÇAKMAK

2022

Batı Karadeniz Tıp Dergisi

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“…Pathological lesions in HS result mainly from the loss of spectrin and/or ankyrin that is normally responsible for anchoring the membrane skeleton in the lipid bilayer. The current knowledge is constantly updated with new mutations resulting in the HS phenotype [10,[37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

“…Many interactions between membrane skeleton proteins and also membrane skeleton proteins with membrane bilayer containing integral membrane proteins via proteins and lipids were discovered due to identification of naturaly occuring mutants which are mostly related to haemolytic anaemias [1][2][3]. These mutants have become the subject of many studies to elucidate the regulatory mechanisms of spectrin-ankyrin interaction, which has significantly increased our knowledge of the structure and function of the erythrocyte membrane skeleton [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Overall, patients with dominant mutations are less affected than those with recessive defects. With the rapid development and wide application of gene diagnostic technologies, the detection rate of HS cases is increasing [10,21]. Most of the mutations arise in exons, but some occur in introns, suggesting that intronic mutations also play a significant role in the pathogenesis of hereditary spherocytosis [22].…”

Section: Introductionmentioning

confidence: 99%

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Spherocytosis-related L1340P mutation in ankyrin affects its interactions with spectrin

Machnicka

Czogalla

Bogusławska

et al. 2022

Preprint

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Previously, we reported a new missense mutation in the ANK1 gene correlated with the HS phenotype. This mutation, resulting in L1340P substitution (HGMD CM149731), likely leads to the changes in the conformation of the ankyrin ZZUD domain important for ankyrin binding to spectrin. In this report, we have shown the molecular and physiological effects of this mutation. First, we assessed the binding activity of human beta-spectrin to the mutated ZZUDL1340P domain of ankyrin using two different experimental approaches: the study of association and dissociation responses of spectrin ankyrin binding domain and sedimentation assay. In addition, we demonstrated changes in morphology caused by the overexpressed ankyrin ZZUD domain in human cell models. Our results prove the key role of L1340 aa residue in the UPA domain for the correct alignment of the ZZUD domain of ankyrin, which results in binding the latter with spectrin within the erythrocyte membrane. Replacing the L1340 with a proline residue disrupts the spectrin binding activity of ankyrin.

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“…During our studies on HS cases in the Polish population [ 29 – 31 ], we identified erythrocyte membrane protein abnormalities in the studied family in which two members (brothers, RK and MK) displayed symptoms of hemolytic anemia that did not fit the characteristics of the known disease [ 32 ]. We used high-throughput sequencing technologies and functional studies to characterize the molecular basis of this anemia case.…”

Section: Introductionmentioning

confidence: 99%

A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5′-nucleotidase deficiency

et al. 2022

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Pyrimidine 5′-nucleotidase deficiency is a rare erythrocyte enzymopathy. Here we report two cases of hemolytic anemia in brothers of Polish origin that are associated with a very rare mutation. Heterozygous deletion in the NT5C3A gene (c.444_446delGTT), inherited most likely from their asymptomatic mother, resulted in a single amino acid residue deletion (p.F149del) in cytosolic pyrimidine 5′-nucleotidase. However, only the mutated transcript was present in the reticulocyte transcriptome of both patients. Only residual activity of pyrimidine 5′-nucleotidase in the brothers’ erythrocytes could be observed when compared with the controls, including their asymptomatic father and sister. Western blot showed no sign of the presence of 5′-nucleotidase protein in the erythrocytes of both studied patients. The 2.5-fold reduction of the purine/pyrimidine ratio observed only in the brothers’ erythrocytes confirms the correlation of the results of molecular analysis, including whole-exome sequencing, with the phenotype of the pyrimidine 5′-nucleotidase deficiency. Altogether, our results may substantiate the hypothesis of the heterogeneity of the molecular basis of the defect involving both the mutation presented here and negative regulation of expression of the “normal” allele.

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Identification of a Novel Mutation of β-Spectrin in Hereditary Spherocytosis Using Whole Exome Sequencing

Cited by 5 publications

References 49 publications

Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience

Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience

Spherocytosis-related L1340P mutation in ankyrin affects its interactions with spectrin

A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5′-nucleotidase deficiency

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