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The Spectrum of SPTA1-Associated Hereditary Spherocytosis
Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or β-spectrin (SPTB). Severe recessive HS is most com...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617536/ https://www.ncbi.nlm.nih.gov/pubmed/31333484 http://dx.doi.org/10.3389/fphys.2019.00815 |
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author | Chonat, Satheesh Risinger, Mary Sakthivel, Haripriya Niss, Omar Rothman, Jennifer A. Hsieh, Loan Chou, Stella T. Kwiatkowski, Janet L. Khandros, Eugene Gorman, Matthew F. Wells, Donald T. Maghathe, Tamara Dagaonkar, Neha Seu, Katie G. Zhang, Kejian Zhang, Wenying Kalfa, Theodosia A. |
author_facet | Chonat, Satheesh Risinger, Mary Sakthivel, Haripriya Niss, Omar Rothman, Jennifer A. Hsieh, Loan Chou, Stella T. Kwiatkowski, Janet L. Khandros, Eugene Gorman, Matthew F. Wells, Donald T. Maghathe, Tamara Dagaonkar, Neha Seu, Katie G. Zhang, Kejian Zhang, Wenying Kalfa, Theodosia A. |
author_sort | Chonat, Satheesh |
collection | PubMed |
description | Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or β-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1-associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1-associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients’ reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression α(LEPRA) allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis, either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1-associated HS and guide toward appropriate management. |
format | Online Article Text |
id | pubmed-6617536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66175362019-07-22 The Spectrum of SPTA1-Associated Hereditary Spherocytosis Chonat, Satheesh Risinger, Mary Sakthivel, Haripriya Niss, Omar Rothman, Jennifer A. Hsieh, Loan Chou, Stella T. Kwiatkowski, Janet L. Khandros, Eugene Gorman, Matthew F. Wells, Donald T. Maghathe, Tamara Dagaonkar, Neha Seu, Katie G. Zhang, Kejian Zhang, Wenying Kalfa, Theodosia A. Front Physiol Physiology Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or β-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1-associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1-associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients’ reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression α(LEPRA) allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis, either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1-associated HS and guide toward appropriate management. Frontiers Media S.A. 2019-07-03 /pmc/articles/PMC6617536/ /pubmed/31333484 http://dx.doi.org/10.3389/fphys.2019.00815 Text en Copyright © 2019 Chonat, Risinger, Sakthivel, Niss, Rothman, Hsieh, Chou, Kwiatkowski, Khandros, Gorman, Wells, Maghathe, Dagaonkar, Seu, Zhang, Zhang and Kalfa. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Chonat, Satheesh Risinger, Mary Sakthivel, Haripriya Niss, Omar Rothman, Jennifer A. Hsieh, Loan Chou, Stella T. Kwiatkowski, Janet L. Khandros, Eugene Gorman, Matthew F. Wells, Donald T. Maghathe, Tamara Dagaonkar, Neha Seu, Katie G. Zhang, Kejian Zhang, Wenying Kalfa, Theodosia A. The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title | The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title_full | The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title_fullStr | The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title_full_unstemmed | The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title_short | The Spectrum of SPTA1-Associated Hereditary Spherocytosis |
title_sort | spectrum of spta1-associated hereditary spherocytosis |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617536/ https://www.ncbi.nlm.nih.gov/pubmed/31333484 http://dx.doi.org/10.3389/fphys.2019.00815 |
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