Héctor M Targovnik

National Scientific and Technical Research Council, Buenos Aires, Buenos Aires F.D., Argentina

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Publications (103)336.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Partial thyroxine-binding globulin deficiency (TBG-PD) is an endocrine defect with a prevalence of 1:4 000 in newborns. Due to the presence of a single TBG gene on the X chromosome, most familial TBG defects follow an X-linked inheritance pattern. Abnormal T4 binding to T4-binding prealbumin (TTR) is a rare cause of euthyroid hyperthyroxinemia, which is transmitted by autosomal dominant inheritance. The purpose of the present study was to identify and characterize new mutations in the Serpina7 and TTR genes in a complete family with typical TBG-PD. All patients underwent clinical and biochemical evaluation. Sequencing of DNA, population screening by (SSCP) analysis, and bioinformatics studies were performed. Molecular studies revealed a novel p.A64D mutation in the exon 1 of Serpina7 gene associated with the previously reported p.A109T mutation in the exon 4 of TTR gene. To our knowledge, this is the first report of a patient with a TBG-PD by a mutation in Serpina7 that was coincident with a mutation in TTR gene that increased affinity of TTR for T4. This work contributes to elucidate the molecular basis of the defects of thyroid hormone transport in serum and the improvement of the diagnosis avoiding unnecessary therapy.
    Hormone and Metabolic Research 12/2013; · 2.15 Impact Factor
  • Source
    Héctor M Targovnik
    Endocrine 10/2013; · 3.53 Impact Factor
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    ABSTRACT: The objetive of this study was to perform genetic analysis in three brothers of Turkish origin born from consanguineus parents and affected by congenital hypothyroidism, goiter and low levels of serum TG. The combination of sequencing of DNA, PCR mapping, quantitative real-time PCR (qPCR), inverse-PCR (I-PCR), multiplex PCR and bioinformatics analysis were used in order to detect TG mutations. We demonstrated that the three affected siblings are homozygous for a DNA inversion of 16,962 bp in the TG gene associated with two deleted regions at both sides of the inversion limits. The inversion region includes the first 9 bp of exon 48, 1,015 bp of intron 47, 191 bp of exon 47, 1,523 bp of intron 46, 135 bp of exon 46 and the last 14,089 bp of intron 45. The proximal deletion corresponds to 27 bp of TG intron 45, while the distal deletion spans the last 230 bp of TG exon 48 and the first 588 bp of intergenic region downstream TG end. The parents were heterozygous carriers of the complex rearrangement. In conclusion, a novel large imperfect DNA inversion within the TG gene was identified by the strategy of I-PCR. This aberration was not detectable by normal sequencing of the exons and exon/intron boundaries. Remarkably, the finding represents the first description of a TG deficiency disease caused by a DNA inversion.
    Molecular and Cellular Endocrinology 08/2013; · 4.04 Impact Factor
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    ABSTRACT: The thyroglobulin (TG) gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. Up to now, 62 inactivating mutations in the TG gene have been identified in patients with congenital goiter and endemic or non-endemic simple goiter. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report 13 patients from 7 unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and imaging evaluation. Single-strand conformation polymorphism (SSCP) analysis, endonuclease restriction analysis, sequencing of DNA, genotyping, population screening, and bioinformatics studies were performed. Molecular analyses revealed seven novel inactivating TG mutations: c.378C>A [p.Y107X], c.2359C>T [p.R768X], c.2736delG [p.R893fsX946], c.3842G>A [p.C1262Y], c.5466delA [p.K1803fsX1833], c.6000C>G [p.C1981W] and c.6605C>G [p.P2183R] and three previously reported mutations: c.886C>T [p.R277X], c.6701C>A [p.A2215D] and c.7006C>T [p.R2317X]. Six patients from two families were homozygous for p.R277X mutation, four were compound heterozygous mutations (p.Y107X/p.C1262Y, p.R893fsX946/p.A2215D, p.K1803fsX1832/p.R2317X), one carried three identified mutations (p.R277X/p.C1981W-p.P2183R) together with a hypothetical micro deletion and the remaining two siblings from another family with typical phenotype had a single p.R768X mutated allele. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of altered TG folding as a consequency of truncated TG proteins and missense mutations located in ACHE-like domain or that replace cysteine.
    Molecular and Cellular Endocrinology 11/2012; · 4.04 Impact Factor
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    ABSTRACT: Iodide organification defect (IOD) is characterized by a reduced ability of the thyroid gland to retain iodide resulting in hypothyroidism. Mutations in thyroid peroxidase (TPO) gene appear to be the most common cause of IOD and are commonly inherited in an autosomal recessive fashion. The TPO gene is located on the chromosome 2p25. It comprises 17 exons, covers approximately 150 kb of genomic DNA and codes 933 amino acids. OBJETIVES: In this study, we characterize the clinical and molecular basis of seven patients from four unrelated families with congenital hypothyroidism (CH) because of IOD. All patients underwent clinical, biochemical and imaging evaluation. The promoter and the complete coding regions of the human TPO along with the flanking intronic regions were analysed by single-strand conformation polymorphism analysis and direct DNA sequencing. Segregation analysis of mutations was carried out, and the effect of the novel missense identified mutations was investigated by 'in silico' studies. All subjects had congenital and persistent primary hypothyroidism. Three novel mutations: c.796C>T [p.Q266X], c.1784G>A [p.R595K] and c.2000G>A [p.G667D] and a previously reported mutation: c.1186_1187insGGCC [p.R396fsX472] have been identified. Four patients were compound heterozygous for p.R396fsX472/p.R595K mutations, two patients were homozygous for p.R595K, and the remaining patient was a compound heterozygous for p.Q266X/p.G667D. Our findings confirm the genetic heterogeneity of TPO defects and the importance of the implementation of molecular studies to determinate the aetiology of the CH with dyshormonogenesis.
    Clinical Endocrinology 04/2012; 76(4):568-76. · 3.40 Impact Factor
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    ABSTRACT: 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. We report a French patient with congenital hypothyroidism, mild enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, genotyping, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the paternal mutation consists of a c.3788-3789insT or c.3788dupT, whereas the maternal mutation consists of g.IVS19+3_+4delAT. Minigene analysis of the g.IVS19+3_+4delAT mutant showed that the exon 19 is skipped during pre-mRNA splicing or partially included by use of cryptic 5' splice site located to 100 nucleotides downstream of the wild type exon-intron junction. The c.3788-3789insT mutation results in a putative truncated protein of 1245 amino acids, whereas g.IVS19+3_4delAT mutation originates two putative truncated proteins of 1330 and 1349 amino acids. In conclusion, we show that the g.IVS19+3_+4delAT mutation promotes the activation of a cryptic donor splice site in the exon 19 of the TG gene. These results open up new perspectives in the knowledge of the mechanism of splicing for the TG pre-mRNA.
    Molecular and Cellular Endocrinology 09/2011; 348(1):313-21. · 4.04 Impact Factor
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    ABSTRACT: Resistance to thyroid hormone (RTH) is characterized by elevated levels of thyroid hormones, normal or slightly increased TSH levels respondent to TRH, resistance to thyroid hormone administration, and variable clinical expression. To describe the diverse clinical and biochemical findings of six children from five unrelated families with molecular diagnosis of RTH (0.5–12.7 years) and their follow-up (3–20 years). All RTH patients and 4 affected parents’ harbored mutations in exons 9 or 10 of the thyroid receptor β gene: p.M313T (de novo), pN331D, p.L341P, p.L346F, and p.P453L. At consultation 5/6 had goiter, 4/6 tachycardia, and 3/5 learning disabilities. Median hormone levels were: T4 257.4 nmol/l (NR: 77.2–180.2); FreeT4 39.9 pmol/(NR:10.3–28.3); T3 4.28 nmol/l (NR:1.23–3.39) TSH 2.8 mUI/l (NR: 0.5–5) always responsive to TRH. TSH levels remained detectable after supraphysiologic T3 administration while SHBG levels showed a paradoxical decrease in 4/6. Thyroid antibodies, initially present in two subjects, became positive in other two during follow-up. All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression). Parent’s thyroid profile showed similar TSH and T3 levels but lower T4 and FT4 than their children. RTH has a distinctive biochemical profile with highly variable clinical manifestations and outcomes. Its recognition and molecular characterization avoid misleading diagnosis. Treatment has to be instituted according to each subject’s own clinical requirements.
    Endocrine 09/2011; · 3.53 Impact Factor
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    ABSTRACT: Resistance to thyroid hormone (RTH) is characterized by elevated levels of thyroid hormones, normal or slightly increased TSH levels respondent to TRH, resistance to thyroid hormone administration, and variable clinical expression. To describe the diverse clinical and biochemical findings of six children from five unrelated families with molecular diagnosis of RTH (0.5-12.7 years) and their follow-up (3-20 years). All RTH patients and 4 affected parents' harbored mutations in exons 9 or 10 of the thyroid receptor β gene: p.M313T (de novo), pN331D, p.L341P, p.L346F, and p.P453L. At consultation 5/6 had goiter, 4/6 tachycardia, and 3/5 learning disabilities. Median hormone levels were: T(4) 257.4 nmol/l (NR: 77.2-180.2); FreeT(4) 39.9 pmol/(NR:10.3-28.3); T(3) 4.28 nmol/l (NR:1.23-3.39) TSH 2.8 mUI/l (NR: 0.5-5) always responsive to TRH. TSH levels remained detectable after supraphysiologic T(3) administration while SHBG levels showed a paradoxical decrease in 4/6. Thyroid antibodies, initially present in two subjects, became positive in other two during follow-up. All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression). Parent's thyroid profile showed similar TSH and T(3) levels but lower T(4) and FT(4) than their children. RTH has a distinctive biochemical profile with highly variable clinical manifestations and outcomes. Its recognition and molecular characterization avoid misleading diagnosis. Treatment has to be instituted according to each subject's own clinical requirements.
    Endocrine 08/2011; 41(1):130-7. · 3.53 Impact Factor
  • Héctor M Targovnik, Cintia E Citterio, Carina M Rivolta
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    ABSTRACT: Human thyroglobulin (TG) gene is a single copy gene, 270 kb long, that maps on chromosome 8q24.2-8q24.3 and contains an 8.5-kb coding sequence divided into 48 exons. TG is exclusively synthesized in the thyroid gland and represents a highly specialized homodimeric glycoprotein for thyroid hormone biosynthesis. Mutations in the TG gene lead to permanent congenital hypothyroidism. The presence of low TG level and also normal perchlorate discharge test in a goitrous individual suggest a TG gene defect. Until now, 52 mutations have been identified and characterized in the human TG gene with functional impact such as structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones. 11 of the mutations affect splicing sites, 11 produce premature stop codons, 23 lead to amino acid changes, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous. The p.R277X, p.C1058R, p.C1977S, p.R1511X, p.A2215D and p.R2223H mutations are the most frequently identified TG mutations. This mini-review focuses on genetic and clinical aspects of TG gene defects.
    Hormone Research in Paediatrics 03/2011; 75(5):311-21. · 1.55 Impact Factor
  • Clinical Endocrinology 12/2010; 74(4):533-5. · 3.40 Impact Factor
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    ABSTRACT: The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99% perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patient's DNA identified the heterozygous duplication GGCC (c.1186_1187insGGCC) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression.
    Arquivos brasileiros de endocrinologia e metabologia 11/2010; 54(8):732-7. · 0.68 Impact Factor
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    ABSTRACT: We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT₄ and TT₃ levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype-phenotype relationships.
    Endocrine 10/2010; 38(3):377-85. · 3.53 Impact Factor
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    ABSTRACT: 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. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29, and TGrI30), one insertion/deletion polymorphism (IndelTG-IVS18), and one exonic single nucleotide polymorphism (c.7589G>A) in 100 AT patients and 100 healthy control subjects. No differences in allele and genotype frequencies distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG-IVS18, and c.7589G>A. However, when we analyzed autoimmune thyroiditis patients with the TGrI29 microsatellite we found a significant association between the 197-bp allele and autoimmune thyroiditis (33.50% vs. 19.00% in control group) (P = 0.001). In addition, a significant major prevalence of the 197/201-bp genotype has been also seen in autoimmune thyroiditis subjects (59% vs. 24% in control group, P < 0.0001). In conclusion, our work showed the association between the thyroglobulin gene and autoimmune thyroiditis in Argentinian population and supports the described evidence of thyroglobulin as a thyroid-specific gene linked to AITD.
    Endocrine 10/2010; 38(3):320-7. · 3.53 Impact Factor
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    ABSTRACT: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Locations included primary care and university hospitals. Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C-->T (p.R277X) and g.IVS35+1delG. For c.886C-->T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes, and together with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility that some cases were introduced to South America from Galicia cannot be excluded.
    The Journal of Clinical Endocrinology and Metabolism 07/2010; 95(7):3522-6. · 6.31 Impact Factor
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    ABSTRACT: Thyroglobulin (TG) defects due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. This dyshormonogenesis displays a wide phenotype variation and is characterized usually by: the presence of congenital goiter or goiter appearing shortly after birth, high (131)I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T(4) and low, normal or high serum T(3). Mutations in TG gene have been also reported associated with endemic and euthyroid nonendemic simple goiter. TG gene defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for mutations. Up to now, 50 mutations have been identified and characterized in the human TG: 23 missense mutations, 10 nonsense mutations, 5 single and 1 large nucleotide deletions, 1 single nucleotide insertion and 10 splice site mutations. The functional consequences of this mutations could be structural changes in the protein molecule that alter the normal protein folding, assembly and biosynthesis of thyroid hormones, leading to a marked reduction in the ability to export the protein from the endoplasmic reticulum.
    Molecular and Cellular Endocrinology 06/2010; 322(1-2):44-55. · 4.04 Impact Factor
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    ABSTRACT: The autoimmune thyroid disease is a complex disorder caused by a combination of genetic susceptibility and environmental factors, which are believed to initiate the autoimmune response to thyroid antigens. Identification of the susceptibility genes has found that unique and diverse genetic factors are in association with Graves' disease and autoimmune thyroiditis. The thyroglobulin gene is an identified thyroid-specific gene associated to autoimmune thyroid disease and, principally, with autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis and thyroglobulin polymorphism markers. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29 and TGrI30), one insertion/deletion (Indel) polymorphism (IndelTG-IVS18) and one exonic single nucleotide polymorphism (SNP) (c.7589G>A) in 122 patients with autoimmune thyroiditis compared with 100 non-related normal subjects. No differences in allele and genotype distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG-IVS18 and c.7589G>A. However, when we analyzed the patients with the TGrI29 microsatellite we found a significant association between the 199-bp allele and AT (33.7% vs. 24.5% in control group) (P = 0.0372). In addition, a higher prevalence of the 201-bp allele has been observed in control subjects (47.5% vs. 38.1% in patients group), although not statistically significant (P = 0.0536). Our work shows the association between the thyroglobulin gene and autoimmune thyroiditis and reinforce that thyroglobulin is a thyroid-specific susceptibility gene for this disease.
    Endocrine 06/2010; 37(3):389-95. · 3.53 Impact Factor
  • Clinical Endocrinology 05/2010; 72(5):716-8. · 3.40 Impact Factor
  • Clinical Endocrinology 09/2009; · 3.40 Impact Factor
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    ABSTRACT: Most of the hemoglobin variants are the result of single amino acid replacement in one of the globin chains. In many cases, these hemoglobinopathies are harmless, while in others they determine alterations in the physical and chemical properties, raising clinical manifestations of variable severity. In the unstable hemoglobinopathies, the changes reduce solubility, inducing the formation of precipitates of denaturated hemoglobin (Heinz bodies), which damage the membrane and finally destroy the red blood cells prematurely. Up to now, more than 150 different unstable hemoglobins have been described; most of them cause chronic hemolysis, increased by infections or drugs. We report the clinical presentation of an unstable hemoglobin (hemoglobin Hammersmith) in a girl with severe hemolytic anemia, splenomegaly and red blood cell requirement.
    Archivos argentinos de pediatría 08/2009; 107(4):347-9. · 0.32 Impact Factor
  • Archivos argentinos de pediatría 08/2009; 107(4):347-349. · 0.32 Impact Factor

Publication Stats

1k Citations
336.03 Total Impact Points

Institutions

  • 2008–2013
    • National Scientific and Technical Research Council
      Buenos Aires, Buenos Aires F.D., Argentina
  • 1991–2012
    • University of Buenos Aires
      • • Faculty of Pharmacy and Biochemistry
      • • Faculty of Medicine
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2010–2011
    • Hospital de Niños Ricardo Gutièrrez
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2007
    • Universidad de Salamanca
      • Department of Medicine
      Helmantica, Castille and León, Spain
  • 2003
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1999
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 1992–1994
    • Free University of Brussels
      • Institute of Interdisciplinary Research (IRIBHM)
      Brussels, BRU, Belgium
    • Dokkyo Medical University
      Totigi, Tochigi, Japan
  • 1985
    • Université Libre de Bruxelles
      • Faculty of Medicine
      Brussels, BRU, Belgium