The Chaperones Involved in Hemoglobin Synthesis Take the Spotlight: Analysis of AHSP in the Argentinean Population and Review of the Literature.

Hemoglobin (Hb) synthesis is a complex, well-coordinated process that requires molecular chaperones. These intervene in different steps: regulating epigenetic mechanisms necessary for the adequate expression of the α- and β-globin clusters, binding the nascent peptides and helping them acquire their native structure, preventing oxidative damage by free globin chains and preventing the cleavage of essential erythroid transcription factors. This study analyzed the distribution of the single nucleotide polymorphism (SNP) rs4296276 in intron 1 of the α-globin chaperone α Hb-stabilizing protein (AHSP) in the Argentinean population.

Two novel unstable hemoglobin variants due to in-frame deletions of key amino acids in the β-globin chain.

Hemoglobinopathies are the most common autosomal recessive disorders and are mostly inherited in a recessive manner. However, certain mutations can affect the globin chain stability, leading to dominant forms of thalassemia. The aim of this work was the molecular and structural characterization of two heterozygous in-frame deletions, leading to β-globin variants in pediatric patients in Argentina.

[Regulation of the β-globin gene family expression, useful in the search for new therapeutic targets for hemoglobinopathies].

Different hemoglobin isoforms are expressed during the embryonic, fetal and postnatal stages. They are formed by combination of polypeptide chains synthesized from the α- and β-globin gene clusters. Based on the fact that the presence of high hemoglobin F levels is beneficial in both sickle cell disease and severe thalassemic syndromes, a revision of the regulation of the β-globin cluster expression is proposed, especially regarding the genes encoding the y-globin chains (HBG1 and HBG2).

Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability.

Two distinct syndromes that link α-thalassemia and intellectual disability (ID) have been described: ATR-X, due to mutations in the ATRX gene, and ATR-16, a contiguous gene deletion syndrome in the telomeric region of the short arm of chromosome 16. A critical region where the candidate genes for the ID map has been established. In a pediatric patient with Hemoglobin H disease, dysmorphic features and ID, 4 novel and clinically relevant Copy Number Variants were identified.

[Molecular bases of α-thalassemia in Argentina].

The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations.

Hb Wilde and Hb Patagonia: two novel elongated beta-globin variants causing dominant beta-thalassemia.

We describe here the molecular and hematological characteristics of novel frameshift mutations in exon 2 of the HBB gene (in heterozygous state) found in two Argentinean pediatric patients with dominant β-thalassemia-like features. In Hb Wilde, HBB:c.270_273delTGAG(p.

Coinheritance of a novel mutation on the HBA1 gene: c.187delG (p.W62fsX66) [codon 62 (-G) (α1)] with the α212 patchwork allele and Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T].

We describe a novel frameshift mutation on the HBA1 gene (c.187delG), causative of α-thalassemia (α-thal) in a Black Cuban family with multiple sequence variants in the HBA genes and the Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] mutation.

Identification of a new HBA1 gene mutation (HBA1:c.301-2A>T) in cis with Hb Riccarton (HBA1:c.154G>A) [α51(CE9)Gly→Ser].

We report two point mutations found in a heterozygous state on the HBA1 gene of an 88-year-old Argentinean patient with an α(+)-thalassemia (α(+)-thal) phenotype: Hb Riccarton HBA1:c.154G>A) [α51(CE9)Gly→Ser] and a novel mutation, HBA1:c.301-2A>T that affects the splicing acceptor site of the second intron and leads to a non functional α-globin chain.

Clinical and genetic characteristics in patients with Huntington's Disease from Argentina.

Unlabelled: Huntington's Disease (HD) is a neurodegenerative disease, caused by the expansion of an unstable (CAG)(n) in the HTT gene. There is scarce data about the disease in Argentina.

Objective: To describe the demographic, clinical and molecular data in patients with HD from Argentina.

Two novel mutations in the thyroglobulin gene as cause of congenital hypothyroidism: identification a cryptic donor splice site in the exon 19.

Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, 52 mutations of the TG gene have been identified in humans. The purpose of the present study was to identify and characterize new mutations in the TG gene.

Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case-control study.

Autoimmune thyroid disease (AITD) is a multifactorial disorder that involves a putative association with thyroid autoantigen-specific and immune regulatory genes, as well as environmental factors. The thyroglobulin gene is the main identified thyroid autoantigen-specific gene associated to autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis (AT) and thyroglobulin polymorphism markers in Argentinian patients.

Two compound heterozygous mutations (c.215delA/c.2422T-->C and c.387delC/c.1159G-->A) in the thyroid peroxidase gene responsible for congenital goitre and iodide organification defect.

Background: Iodide organification defects are frequently but not always associated with mutations in the thyroid peroxidase (TPO) gene and characterized by a positive perchlorate discharge test. These mutations phenotypically produce a congenital goitrous hypothyroidism, with an autosomal recessive mode of inheritance.

Objectives: In the present study we extended our initial molecular studies in six unrelated patients heterozygous for the TPO mutations, in order to identify the second mutation in this autosomal recessive disease.

Three mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect.

Background: Iodide organification defects are associated with mutations in the dual oxidase 2 (DUOX2) gene and are characterized by a positive perchlorate discharge test. These mutations produce a congenital goitrous hypothyroidism, usually transmitted in an autosomal recessive mode.

Methods: We studied the complete coding sequence of the human DUOX2 gene by single-strand conformational polymorphism (SSCP) analysis of DNA from 17 unrelated patients with iodide organification defects.

[The thyroid as a model for molecular mechanisms in genetic diseases].

Thyroid diseases constitute a heterogeneous collection of abnormalities associated with mutations in genes responsible for the development of thyroid: thyroid transcription factor-1 (TTF-1), thyroid transcriptions factor-2 (TTF-2) and PAX8, or in one of the genes coding for the proteins involved in thyroid hormone biosynthesis such as thyroglobulin (TG), thyroperoxidase (TPO), hydrogen peroxide-generating system (DUOX2), sodium/iodide symporter (NIS), pendrin (PDS), TSH and TSH receptor (TSHr). Congenital hypothyroidism occurs with a prevalence of 1 in 4000 newborns. Patients with this syndrome can be divided into two groups: nongoitrous (dysem/bryogenesis) or goitrous (dyshormonogenesis) congenital hypothyroidism.

A new case of congenital goiter with hypothyroidism caused by a homozygous p.R277X mutation in the exon 7 of the thyroglobulin gene: a mutational hot spot could explain the recurrence of this mutation.

Identification of thyroglobulin (TG) gene mutations may provide insight into the structure-function relationship. In this study, we have performed molecular studies in a patient with congenital goiter, hypothyroidism, and impairment of TG synthesis. Genomic DNA sequencing revealed a homozygous c.

The molecular basis of beta-thalassemia in Argentina. Influence of the pattern of immigration from the Mediterranean Basin.

In order to determine the molecular heterogeneity of the beta-thalassemia gene and to analyze the influence of immigration from the Mediterranean Basin, a total of 254 families (475 subjects) from Argentinean beta-thalassemia patients were investigated using molecular biology techniques. This allowed us to provide a simplified diagnosis and genetic counselling of this disorder in Argentina.

Two distinct compound heterozygous constellations (R277X/IVS34-1G>C and R277X/R1511X) in the thyroglobulin (TG) gene in affected individuals of a Brazilian kindred with congenital goiter and defective TG synthesis.

In this study, we have extended our initial molecular studies of a nonconsanguineous family with two affected siblings and one of their nephews with congenital goiter, hypothyroidism, and marked impairment of thyroglobulin synthesis. Genomic DNA sequencing revealed that the index patient (affected nephew) was heterozygous for a single base change of a cytosine to a thymine at nucleotide 886 in exon 7 (886C>T, mother's mutation) in one allele and for a novel guanine to cytosine transversion at position -1 of the splice acceptor site in intron 34 (IVS34-1G>C, father's mutation) in the other allele. The two affected siblings inherited the 886C>T mutation from their mother and a previously reported cytosine to thymine transition at nucleotide 4588 in exon 22 from their father (4588C>T).

Five novel inactivating mutations in the thyroid peroxidase gene responsible for congenital goiter and iodide organification defect.

Thyroid peroxidase (TPO) defects, typically transmitted as autosomal recessive traits, result in hypothyroid goiters with failure to convert iodide into organic iodine. We analyzed the TPO gene in 14 unrelated patients with clinical evidence of iodide organification defects. Seven of the affected individuals harbored mutations in the TPO gene; one was compound heterozygous, the others were simply heterozygous for TPO mutations.

Identification and characterization of a novel large insertion/deletion polymorphism of 1464 base pair in the human thyroglobulin gene.

We identified a novel large insertion/deletion (Indel) polymorphism of 1464 bp localized in intron 18 of the human thyroglobulin gene. Data from sequence showed a high A+T content (62%), two 17-bp long motif repeats, and three different types of 10-bp long palindromic sequences. The comparison between these 1464 bp and sequences deposited in National Center for Biotechnology Information (NCBI)/GenBank database exhibit a nonsignificant degree of homology with any previously described sequences.