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Hematology, Transfusion and Cell Therapy 2020
PubMed: 31080003
DOI: 10.1016/j.htct.2019.01.005 -
American Journal of Hematology Oct 2022
Topics: Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Humans; Spectrin; Spherocytosis, Hereditary
PubMed: 35834292
DOI: 10.1002/ajh.26662 -
Hematology Reports Oct 2022Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal...
Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal jaundice and severe hemolytic anemia. A peripheral smear examination showed severe anisopoikylocytosis. DNA sequencing revealed compound double heterozygous for mutant α-spectrin SPTA1 (Arg28His) and homozygous αLELY polymorphism (low expression α-spectrin allele), compatible with diagnosis of HPP.The patient required a blood transfusion initially, but spontaneously improved after two years. Our case illustrates that, despite the presence of the allele αLELY in homozygous, the clinical phenotype is similar to cases with a mutation in SPTA1 associated with αLELY in trans.
PubMed: 36278520
DOI: 10.3390/hematolrep14040043 -
British Journal of Haematology May 2019
Novel mutations in SPTA1 and SPTB identified by whole exome sequencing in eight Thai families with hereditary pyropoikilocytosis presenting with severe fetal and neonatal anaemia.
Topics: Adolescent; Anemia, Neonatal; Child; Child, Preschool; Elliptocytosis, Hereditary; Family; Female; Fetal Diseases; Humans; Infant; Male; Spectrin; Thailand; Exome Sequencing
PubMed: 30198572
DOI: 10.1111/bjh.15559 -
American Journal of Human Genetics Aug 1996Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are inherited disorders of erythrocyte shape that are frequently associated with abnormalities in...
Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are inherited disorders of erythrocyte shape that are frequently associated with abnormalities in alpha-spectrin, one of the principal structural proteins of the erythrocyte membrane skeleton. Five polymorphisms of the alpha-spectrin gene, located in a 6-kb interval of genomic DNA, were identified and analyzed in normal and mutant alpha-spectrin alleles. Three of these polymorphisms are due to single nucleotide substitutions in the alpha-spectrin gene coding region that lead to changes in the amino acid sequence. In combination, these three polymorphisms are responsible for the different peptide phenotypes of the alphaII domain previously observed following limited tryptic digestion of spectrin protein. The most common haplotype, type 1, was found predominantly in Caucasians and was the only haplotype identified in Asians. Haplotypes 2, 3, and 4 were identified predominantly in individuals of African ancestry and were commonly found in patients with HE or HPP. Analysis of coinheritance of alphaII domain polymorphisms with alpha-spectrin gene mutations causing HE or HPP in African-American patients with HE and HPP suggests that, with one exception, a given HE/HPP mutation is present in an alpha-spectrin gene of only one haplotype, indicating a founder effect. The other two polymorphisms located in this region of the alpha-spectrin gene do not change the amino acid sequence of the encoded alpha-spectrin chain and are not in linkage disequilibrium with three of the four alphaII domain haplotypes. A model is proposed for the evolutionary origin of the different haplotypes.
Topics: Amino Acid Sequence; Anemia, Hemolytic, Congenital; Asian; Asian People; Base Sequence; Biological Evolution; Black People; Elliptocytosis, Hereditary; Erythrocytes, Abnormal; Haplotypes; Humans; Models, Genetic; Molecular Sequence Data; Mutagenesis, Insertional; Polymorphism, Genetic; Prevalence; Repetitive Sequences, Nucleic Acid; Spectrin; United States; White People
PubMed: 8755921
DOI: No ID Found -
Cytometry. Part B, Clinical Cytometry Jul 2008Flow cytometric analysis of eosin-5-maleimide (EMA)-labeled red blood cells (RBCs) has been used as a screening test for the diagnosis of patients with hereditary...
BACKGROUND
Flow cytometric analysis of eosin-5-maleimide (EMA)-labeled red blood cells (RBCs) has been used as a screening test for the diagnosis of patients with hereditary spherocytosis (HS). We assessed the fluorescence profiles for patients having HS and hereditary pyropoikilocytosis (HPP) together with their red cell indices.
METHODS
Flow cytometry was used to analyze EMA-labeled RBCs. Membrane protein defects and spectrin variants were identified by SDS-polyacrylamide gel electrophoresis.
RESULTS
An overlay of single fluorescence peaks for normal individuals, and those with HS and HPP revealed a graded fluorescence intensity (normal > HS > HPP). The area under each peak defined a specific RBC subpopulation; namely, normal RBCs, spherocytes, and microspherocytes. HS RBCs having a gross reduction in band 3 or spectrin content gave fluorescence readings almost as low as those for HPP. Complex fluorescence profiles were obtained for isolated HS and HPP cases.
CONCLUSIONS
The mean cell volume is a useful discriminator for HS and HPP. We presented evidence that a mixed RBC population could occur in some HS and HPP patients, either in a transient manner or for a long-term period. A differential diagnostic scheme for detecting HPP and HS by flow cytometry is proposed.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic, Congenital; Child; Child, Preschool; Diagnosis, Differential; Eosine Yellowish-(YS); Erythrocyte Membrane; Erythrocytes, Abnormal; Female; Flow Cytometry; Humans; Infant; Male; Middle Aged; Spectrin; Spherocytosis, Hereditary
PubMed: 18454487
DOI: 10.1002/cyto.b.20413 -
Blood Jun 1990Defects involving alpha spectrin (Sp) are found in patients with hereditary elliptocytosis and a related disorder, hereditary pyropoikilocytosis (HPP). We have...
Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis.
Defects involving alpha spectrin (Sp) are found in patients with hereditary elliptocytosis and a related disorder, hereditary pyropoikilocytosis (HPP). We have previously found that the severity of hemolysis was related to the total spectrin content of the cells and the percentage of unassembled dimeric Sp (SpD) in the membranes, which, in turn, reflected the amount of mutant Sp in the cell. However, no data are available comparing differences in the function of various alpha Sp mutations to clinical severity. We now report studies of nine homozygotes or double heterozygotes for four alpha Sp mutations: alpha 1/74, alpha 1/46, alpha 1/65, and alpha 1/61, whose red blood cells (RBCs) contained only the mutant Sp and no normal Sp. Sp alpha 1/74, Sp alpha 1/46, and alpha 1/65 homozygotes differed strikingly in the severity of hemolysis that correlated with the severity of mutant Sp dysfunction, as reflected by the fraction of unassembled SpD in the membranes and the self-association of mutant Sp on inside-out vesicles. Homozygotes for Sp alpha 1/74 had a very severe hemolytic anemia and their SpD were virtually incapable of self-association, whereas SpD alpha 1/46 were not as severely affected. The Sp alpha 1/65 homozygotes had a relatively mild hemolytic anemia and their SpD showed the least impairment of function. Ultrastructural examination of membrane skeletons from subjects whose SpD self-association was severely impaired showed gross skeletal disruption and loss of hexagonal structure. In striking contrast, the homozygote for the mildly dysfunctional Sp alpha 1/65 had only a moderate disruption of the skeleton. Some of the homozygous or doubly heterozygous subjects also exhibited a partial deficiency of Sp that correlated with a RBC morphology characteristic of HPP, namely, marked microspherocytosis with virtual absence of elliptocytes. These data demonstrate striking differences in the function and structure of various alpha Sp mutants that underlie differences in clinical expression.
Topics: Adolescent; Adult; Child; Child, Preschool; Cytoskeleton; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes, Abnormal; Female; Hematologic Diseases; Heterozygote; Homozygote; Humans; Male; Microscopy, Electron; Mutation; Pedigree; Phenotype; Spectrin
PubMed: 2346784
DOI: No ID Found -
American Journal of Hematology May 2021
Topics: Anemia, Hypochromic; Cells, Cultured; Child; Elliptocytosis, Hereditary; Exons; Female; Frameshift Mutation; Genetic Association Studies; Heterozygote; Humans; Jaundice; Male; Middle Aged; Myelodysplastic Syndromes; Point Mutation; Protein Conformation; Sickle Cell Trait; Spectrin; beta-Globins
PubMed: 33556202
DOI: 10.1002/ajh.26121 -
Blood Apr 1990We describe a white French family in which 12 subjects presented with hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP). Eight of these subjects were...
Hereditary pyropoikilocytosis and elliptocytosis in a white French family with the spectrin alpha I/74 variant related to a CGT to CAT codon change (Arg to His) at position 22 of the spectrin alpha I domain.
We describe a white French family in which 12 subjects presented with hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP). Eight of these subjects were shown to be heterozygous for a spectrin (Sp) alpha I/74 variant, as demonstrated by analysis of partial tryptic digestion fragments of spectrin. This abnormal peptide pattern was associated with a decreased ability of Sp dimers to self-associate. In this kindred, in which four generations were available for study, the clinical expression varied from mild HE to HPP with an intermediate status of hemolytic HE. The severity of the disease appeared to be correlated both with the estimated amount of variant Sp (42% to 65%) and the excess of Sp dimers found in the membrane (30% to 51%, with a normal value of 3.7% +/- 1.6%). Reassociation studies using isolated Sp alpha and beta chains from an affected patient and an unaffected control subject showed that the Sp alpha I/74 Kd abnormal tryptic peptide resulted from a defect in the Sp alpha chain. Partial amino acid sequencing showed that the Sp alpha I/74 Kd peptide resulted from cleavage at lysine residue 42 of the Sp alpha I/80 Kd domain. Knowledge of the exon/intron organization of the human alpha Sp gene allowed us to amplify by the polymerase chain reaction the second exon of the alpha Sp gene in total cellular DNA of the HPP proposita. The amplified fragment was subcloned and sequenced. We found a G to A base substitution in the 22nd codon (CAT for CGT), which changes the normal arginine to a histidine. Hybridization of amplified DNAs with allele-specific oligonucleotides corresponding to the normal and mutant sequences confirmed the presence of the mutation in six other HE and HPP members of the family. The identification of this mutation at the DNA level confirmed the transmission of the same molecular defect in Sp through four generations but with different patterns of clinical expression.
Topics: Adult; Aged; Alleles; Amino Acid Sequence; Anemia, Hemolytic, Congenital; Base Sequence; Codon; DNA; Elliptocytosis, Hereditary; Erythrocyte Count; Erythrocyte Deformability; Erythrocyte Membrane; Female; Genetic Variation; Humans; Male; Membrane Proteins; Middle Aged; Molecular Sequence Data; Oligonucleotides; Pedigree; Polymerase Chain Reaction; RNA, Messenger; Spectrin; Trypsin
PubMed: 2328319
DOI: No ID Found -
Blood Sep 1993Hereditary pyropoikilocytosis (HPP) is a recessively inherited hemolytic anemia characterized by severe poikilocytosis and red blood cell fragmentation. HPP red blood...
Hereditary pyropoikilocytosis (HPP) is a recessively inherited hemolytic anemia characterized by severe poikilocytosis and red blood cell fragmentation. HPP red blood cells are partially deficient in spectrin and contain a mutant alpha or beta-spectrin that is defective in terms of spectrin self-association. Although the nature of the latter defect has been studied in considerable detail and many mutations of alpha-spectrin and beta spectrin have been identified, the molecular basis of spectrin deficiency is unknown. Here we report two mechanisms underlying spectrin deficiency in HPP. The first mechanism involves a thalassemia-like defect characterized by a reduced synthesis of alpha-spectrin as shown by studies involving synthesis of spectrin in two unrelated HPP probands and their parents: One parent carries the elliptocytogenic spectrin mutation, whereas the other parent is fully asymptomatic. Peripheral blood mononuclear cells as a source of erythroid burst-forming unit (BFUe) were cultured in a two-phase liquid culture system that gives rise to terminally differentiated erythroblasts. Pulse-labeling studies of an equal number of erythroblasts or morphologically identical maturity showed that the synthesis of alpha-spectrin as well as the mRNA levels as measured by the competitive polymerase chain reaction (PCR) method are markedly reduced in the presumed asymptomatic carriers and the HPP probands. In contrast, the synthesis and mRNA levels of beta-spectrin were normal. These results constitute a direct demonstration of an alpha-spectrin synthetic defect in a subset of asymptomatic carriers of HPP and HPP probands. The second mechanism underlying spectrin deficiency involves increased degradation of mutant spectrin before its assembly on the membrane. This is evidenced by pulse labeling studies of erythroblasts from a patient with HPP associated with a homozygous state for spectrin alpha I/46 mutation (leu-pro mutation at AA 207 of alpha-spectrin). These studies showed that although spectrin is synthesized in the cytosol in normal amounts, the rate of turnover of alpha-spectrin is faster resulting in about 40% to 50% reduced assembly of alpha-spectrin and beta-spectrin on the membrane. Thus, spectrin deficiency in this case is at least in part caused by increased susceptibility of the mutant spectrin to degradation before its assembly on the membrane. We conclude that at least two separate mechanisms underlie the molecular basis of spectrin deficiency in HPP.
Topics: Adolescent; Adult; Anemia, Hemolytic, Congenital; Base Sequence; Cells, Cultured; Erythroblasts; Erythrocytes; Erythrocytes, Abnormal; Female; Humans; Membrane Proteins; Molecular Sequence Data; Mutation; RNA, Messenger; Spectrin
PubMed: 8364214
DOI: No ID Found