The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

Satheesh Chonat,Donald T Wells,Eugene Khandros,Haripriya Sakthivel,Stella T Chou,Jennifer A Rothman,Theodosia A Kalfa,Matthew F Gorman,Janet L Kwiatkowski,Wenying Zhang,Kejian Zhang,Katie G Seu,Neha Dagaonkar,Tamara Maghathe,Mary Risinger,Omar Niss,Loan Hsieh

doi:10.3389/fphys.2019.00815

Abstract

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 αLEPRA 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.

Highlights

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) cytoskeleton disorder causing hereditary hemolytic anemia (HHA), characterized by sphere-shaped erythrocytes with increased osmotic fragility
DNA was isolated from peripheral blood, and analyzed on an Next Generation Sequencing (NGS) HHA panel; the regions of interest for enrichment and DNA sequencing included the coding exons plus 20 bases of intronic boundaries for 32 genes known to be associated with RBC membrane and enzyme disorders and with congenital dyserythropoietic anemias: ABCG5, ABCG8, AK1, ALDOA, ANK1, C15orf41, CDAN1, EPB41, EPB42, G6PD, GATA1, GCLC, GPI, GPX1, GSR, GSS, HK1, KIF23, KLF1, NT5C3A, PFKM, PGK1, PIEZO1, PKLR, RHAG, SEC23B, SLC2A1(GLUT1), SLC4A1, SPTA1, SPTB, TPI1, and XK
The heterozygous parents did not have any evidence of hemolytic anemia as expected, since even αLELY in trans to a null SPTA1 allele, producing a total of ∼25% of normal α-spectrin, causes no disease (Delaunay et al, 2004)

Summary

INTRODUCTION

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) cytoskeleton disorder causing hereditary hemolytic anemia (HHA), characterized by sphere-shaped erythrocytes (spherocytes) with increased osmotic fragility. The alternative splicing results in frameshift and premature termination of translation, leading to decreased α-spectrin production This allele (MAF of 0.5% per gnomad.broadinstitute.org) produces only about 16% of full-length spectrin as compared to the normal SPTA1 allele, based on studies with metabolic labeling of erythroblasts in vitro (Wichterle et al, 1996). ΑLEPRA in trans to a null SPTA1 allele (leading to a total α-spectrin production of about 8%) has been shown to cause severe autosomal recessive HS, with anemia and jaundice that resolve with splenectomy (Wichterle et al, 1996; Delaunay et al, 2004). We present here eleven patients with HS due to α-spectrin deficiency and discuss their phenotype/genotype correlation (Table 1)

MATERIALS AND METHODS

RESULTS AND DISCUSSION

ETHICS STATEMENT