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1.
Pediatr Blood Cancer ; 64(3)2017 03.
Article in English | MEDLINE | ID: mdl-27718309

ABSTRACT

We describe the second patient with anionic exchanger 1/band 3 null phenotype (band 3 nullVIENNA ), which was caused by a novel nonsense mutation c.1430C>A (p.Ser477X) in exon 12 of SLC4A1. We also update on the previous band 3 nullCOIMBRA patient, thereby elucidating the physiological implications of total loss of AE1/band 3. Besides transfusion-dependent severe hemolytic anemia and complete distal renal tubular acidosis, dyserythropoiesis was identified in the band 3 nullVIENNA patient, suggesting a role for band 3 in erythropoiesis. Moreover, we also, for the first time, report that long-term survival is possible in band 3 null patients.


Subject(s)
Acidosis, Renal Tubular/etiology , Anemia, Hemolytic/etiology , Anion Exchange Protein 1, Erythrocyte/genetics , Codon, Nonsense/genetics , Erythrocytes, Abnormal/pathology , Acidosis, Renal Tubular/pathology , Anemia, Hemolytic/pathology , Child, Preschool , Erythropoiesis , Homozygote , Humans , Male , Prognosis
2.
Blood Cells Mol Dis ; 60: 18-23, 2016 09.
Article in English | MEDLINE | ID: mdl-27519939

ABSTRACT

Glucose-6-phosphate isomerase (GPI) deficiency cause hereditary nonspherocytic hemolytic anemia (HNSHA) of variable severity in individuals homozygous or compound heterozygous for mutations in GPI gene. This work presents clinical features and genotypic results of two patients of Portuguese origin with GPI deficiency. The patients suffer from a mild hemolytic anemia (Hb levels ranging from 10 to 12.7g/mL) associated with macrocytosis, reticulocytosis, hyperbilirubinemia, hyperferritinemia and slight splenomegaly. Genomic DNA sequencing revealed in one patient homozygosity for a new missense mutation in exon 3, c.260G>C (p.Gly87Ala), and in the second patient compound heterozygosity for the same missense mutation (p.Gly87Ala), along with a frameshift mutation resulting from a single nucleotide deletion in exon 14, c.1238delA (p.Gln413Arg fs*24). Mutation p.Gln413Arg fs*24 is the first frameshift null mutation to be described in GPI deficiency. Molecular modeling suggests that the structural change induced by the p.Gly87Ala pathogenic variant has direct impact in the structural arrangement of the region close to the active site of the enzyme.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Frameshift Mutation , Glucose-6-Phosphate Isomerase/genetics , Mutation, Missense , Catalytic Domain , Humans , Models, Molecular , Portugal , Protein Conformation , Sequence Analysis, DNA
3.
Stem Cell Reports ; 5(6): 1053-1066, 2015 Dec 08.
Article in English | MEDLINE | ID: mdl-26549847

ABSTRACT

Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Erythroid Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Pyruvate Kinase/deficiency , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/genetics , Pyruvate Metabolism, Inborn Errors/therapy , Alleles , Base Sequence , Cell Count , DNA, Complementary/genetics , Erythroid Cells/metabolism , Gene Targeting , Genetic Therapy , Humans , Leukocytes, Mononuclear/metabolism , Recombination, Genetic
4.
Eur J Haematol ; 91(4): 361-8, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23859443

ABSTRACT

INTRODUCTION: Congenital erythrocytosis can be classified as primary, when the defect is intrinsic to the RBC progenitors and independent of the serum erythropoietin (Epo) concentration, or secondary, when the erythrocytosis is the result of an upregulation of Epo production. Primary erythrocytosis is associated with mutations in the EPOR gene, secondary CE can de due to mutations that stabilize the hemoglobin in the oxygenated form or to mutations in the genes that control the transcriptional activation of the EPO gene - VHL, EGLN1, EPAS1. Chuvash polycythemia, caused by mutations in VHL gene, shares features of both primary and secondary erythrocytosis, with increased Epo production but also hypersensitivity of progenitors to Epo. MATERIAL AND METHODS: With the main objective of describing the etiology and molecular basis of CE, we have studied 70 consecutive unrelated patients presenting with idiopathic erythrocytosis from our hematology clinic or referred from other centers. According to a study algorithm, we have sequenced all the genes described as associated with CE. RESULTS AND DISCUSSION: Erythrocytosis molecular etiology was identify in 25 (36%) of the 70 subjects. High-affinity Hb variants were the most common cause, present in 20% of the cases. New mutations were identified in the JAK2, EPOR, VHL, and EGLN1 genes. CONCLUSIONS: High-affinity hemoglobin variants are a very rare cause of secondary CE, but it seems likely that their incidence may be underestimated. Our experience shows that in erythrocytosis with a dominant inheritance and normal or inappropriate high Epo levels, the HBB and HBA genes should be the first to be studied. In spite of the seven genes known to be involved in CE, the majority of the cases have unknown etiology.


Subject(s)
Carrier Proteins/genetics , Hemoglobins, Abnormal/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Janus Kinase 2/genetics , Mutation , Polycythemia/genetics , Receptors, Erythropoietin/genetics , Adolescent , Adult , Aged , Child , Cytoskeletal Proteins , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Molecular Biology , Molecular Chaperones , Oxygen/metabolism , Polycythemia/congenital , Polycythemia/diagnosis
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