IVO JORGE PRADO ARNHOLD
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
9 resultados
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- Genetic Predictors of Long-Term Response to Growth Hormone (GH) Therapy in Children With GH Deficiency and Turner Syndrome: The Influence of a SOCS2 Polymorphism(2014) BRAZ, Adriana F.; COSTALONGA, Everlayny F.; TRARBACH, Ericka B.; SCALCO, Renata C.; MALAQUIAS, Alexsandra C.; GUERRA-JUNIOR, Gil; ANTONINI, Sonir R. R.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. Objective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P < .003), GHR-exon 3 (P = .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.
- Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature(2019) FREIRE, Bruna L.; HOMMA, Thais K.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; VASQUES, Gabriela A.; MALAQUIAS, Alexsandra C.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Context: Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants. Objective: To perform a genetic investigation of children with isolated short stature born SGA. Design: Screening by exome (n = 16) or targeted gene panel (n = 39) sequencing. Setting: Tertiary referral center for growth disorders. Patients and Methods: We selected 55 patients born SGA with persistent short stature without an identified cause of short stature. Main Outcome Measures: Frequency of pathogenic findings. Results: We identified heterozygous pathogenic or likely pathogenic genetic variants in 8 of 55 patients, all in genes already associated with growth disorders. Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1), and two are involved in the RAS/MAPK pathway, PTPN11 (n = 1) and NF1 (n = 1). None of these patients had clinical findings that allowed for a clinical diagnosis. Seven patients were SGA only for length and one was SGA for both length and weight. Conclusion: These genomic approaches identified pathogenic or likely pathogenic genetic variants in 8 of 55 patients (15%). Six of the eight patients carried variants in genes associated with growth plate development, indicating that mild forms of skeletal dysplasia could be a cause of growth disorders in this group of patients.
- Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature(2013) VASQUES, Gabriela A.; AMANO, Naoko; DOCKO, Ana J.; FUNARI, Mariana F. A.; QUEDAS, Elisangela P. S.; NISHI, Mirian Y.; ARNHOLD, Ivo J. P.; HASEGAWA, Tomonobu; JORGE, Alexander A. L.Context: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). Objective: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. Patients and Methods: The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. Results: Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 mu g/kg.d) without significant height SD score change during therapy. Conclusions: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.
- Increased Transactivation Associated with SOX3 Polyalanine Tract Deletion in a Patient with Hypopituitarism(2011) ALATZOGLOU, Kyriaki S.; KELBERMAN, Daniel; COWELL, Christopher T.; PALMER, Rodger; ARNHOLD, Ivo J. P.; MELO, Maria E.; SCHNABEL, Dirk; GRUETERS, Annette; DATTANI, Mehul T.Backgound and Aims: Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. Methods: We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable septooptic dysplasia were screened for variability of the PA tract. Results: We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress beta-catenin mediated transcription in vitro. Conclusion: This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation. (J Clin Endocrinol Metab 96: E685-E690, 2011)
- The Interactive Effect of GHR-Exon 3 and -202 A/C IGFBP3 Polymorphisms on rhGH Responsiveness and Treatment Outcomes in Patients with Turner Syndrome(2012) BRAZ, Adriana F.; COSTALONGA, Everlayny F.; MONTENEGRO, Luciana R.; TRARBACH, Ericka B.; ANTONINI, Sonir R. R.; MALAQUIAS, Alexsandra C.; RAMOS, Ester S.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Context: There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. Objective: The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short-and long-term outcomes of rhGH therapy in patients with TS. Design and Patients: GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 +/- 2.5 yr of rhGH treatment. Main Outcome Measures: First-year growth velocity and adult height were measured. Results: Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R-2 = 0.27; -202 A/C IGFBP3, R-2 = 0.24; the combined genotypes, R-2 = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. Conclusion: Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with TS.
- Absence of GH-Releasing Hormone (GHRH) Mutations in Selected Patients with Isolated GH Deficiency(2011) FRANCA, Marcela M.; JORGE, Alexander A. L.; ALATZOGLOU, Kyriaki S.; CARVALHO, Luciani R. S.; MENDONCA, Berenice B.; AUDI, Laura; CARRASCOSA, Antonio; DATTANI, Mehul T.; ARNHOLD, Ivo J. P.Context: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency. Objective: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD. Patients and Methods: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers. Seventy-two patients fulfilled all the following criteria: severe short stature (height SD score <= -2.5), low peakGHafter stimulation (peak <= 5 ng/ml), eutopic posterior pituitary lobe, and absence of mutations in GH1 and GHRHR and therefore were strong candidates for GHRH mutations. The coding sequence and splice sites of GHRH were amplified by PCR with intronic primers and sequenced. Results: In five of 151 patients (four of 42 from Brazil), the GHRH c. 223 C>T, p. L75F change was identified in heterozygosity. This variant has been previously reported as a polymorphism and is more frequent in African than European and Asian populations. Six allelic variants (five novel) that do not predict change of amino acids or splice sites were identified in five patients: c. 147 C>T, p.S49S, IVS1 -70 G>A, IVS1 -74 T>C, IVS3 -47 del1, and IVS3 +7 G>A/IVS3 + 41 G>A. No functional mutations were found in this cohort. Conclusions: GHRH mutations were not identified in a selected cohort of patients with IGHD, suggesting that, if they exist, they may be an extremely rare cause of IGHD. Other, as-yet-unidentified genetic factors may be implicated in the genetic etiology of IGHD in our cohort. (J Clin Endocrinol Metab 96: E1457-E1460, 2011)
- Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development(2019) BATISTA, Rafael Loch; INACIO, Marlene; ARNHOLD, Ivo Jorge Prado; GOMES, Nathalia Lisboa; FARIA JR., Jose Antonio Diniz; MORAES, Daniela Rodrigues de; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoContext: In 46,XY disorders of sexual development (DSD) patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but their roles not completely understood yet. Design: A total of 144 individuals (18 to 60 years of age) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology. Results: We found a positive association between prenatal androgen exposure and male psychosexual outcomes. Alternatively, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There were 19% (n = 27) with gender change, which was associated with prenatal androgen exposure (P < 0.001) but not with the external genital virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier. Conclusions: Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, whereas the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be followed for gender issues in their management.
- Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3(2014) MACEDO, Delanie B.; ABREU, Ana Paula; REIS, Ana Claudia S.; MONTENEGRO, Luciana R.; DAUBER, Andrew; BENEDUZZI, Daiane; CUKIER, Priscilla; SILVEIRA, Leticia F. G.; TELES, Milena G.; CARROLL, Rona S.; GUERRA JUNIOR, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran; ARNHOLD, Ivo J. P.; CASTRO, Margaret de; MOREIRA, Ayrton C.; MARTINELLI JR., Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONCA, Berenice B.; BRITO, Vinicius N.; ANTONINI, Sonir R.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.
- Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development(2022) GOMES, Nathalia Lisboa; BATISTA, Rafael Loch; NISHI, Mirian Y.; LERARIO, Antonio Marcondes; SILVA, Thatiana E.; NARCIZO, Amanda de Moraes; BENEDETTI, Anna Flavia Figueredo; FUNARI, Mariana Ferreira de Assis; FARIA JUNIOR, Jose Antonio; MORAES, Daniela Rodrigues; QUINTAO, Lia Mesquita Lousada; MONTENEGRO, Luciana Ribeiro; FERRARI, Maria Teresa Martins; JORGE, Alexander A.; ARNHOLD, Ivo J. P.; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoContext Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). Objective To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. Design/patients 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. Results Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. Conclusions The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD.