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
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- 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)
- Molecular and Gene Network Analysis of Thyroid Transcription Factor 1 (TTF1) and Enhanced at Puberty (EAP1) Genes in Patients with GnRH-Dependent Pubertal Disorders(2013) CUKIER, Priscilla; WRIGHT, Hollis; RULFS, Tomke; SILVEIRA, Leticia Ferreira Gontijo; TELES, Milena Gurgel; MENDONCA, Berenice Bilharinho; ARNHOLD, Ivo J. P.; HEGER, Sabine; LATRONICO, Ana Claudia; OJEDA, Sergio R.; BRITO, Vinicius NahimeBackground/Aim: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. Patients and Methods: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta-network framework GeneMANIA and Cytoscape software. Results: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5'-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. Conclusion: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks. (C) 2013 S. Karger AG, Basel
- High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency(2021) GERGICS, Peter; SMITH, Cathy; BANDO, Hironori; JORGE, Alexander A. L.; ROCKSTROH-LIPPOLD, Denise; VISHNOPOLSKA, Sebastian A.; CASTINETTI, Frederic; MAKSUTOVA, Mariam; CARVALHO, Luciani Renata Silveira; HOPPMANN, Julia; MAYER, Julian Martinez; ALBAREL, Frederique; BRASLAVSKY, Debora; KESELMAN, Ana; BERGADA, Ignacio; MARTI, Marcelo A.; SAVEANU, Alexandru; BARLIER, Anne; JAMRA, Rami Abou; GUO, Michael H.; DAUBER, Andrew; NAKAGUMA, Marilena; MENDONCA, Berenice B.; JAYAKODY, Sajini N.; OZEL, A. Bilge; FANG, Qing; MA, Qianyi; LI, Jun Z.; BRUE, Thierry; MILLAN, Maria Ines Perez; ARNHOLD, Ivo J. P.; PFAEFFLE, Roland; KITZMAN, Jacob O.; CAMPER, Sally A.Pituitary hormone deficiency occurs in similar to 1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
- Functional Impact of Novel Androgen Receptor Mutations on the Clinical Manifestation of Androgen Insensitivity Syndrome(2017) PETROLI, Reginaldo J.; HIORT, Olaf; STRUVE, Dagmar; GESING, Julia K.; SOARDI, Fernanda C.; SPINOLA-CASTRO, Angela M.; MELO, Karla; ARNHOLD, Ivo J. Prado; MACIEL-GUERRA, Andrea T.; GUERRA-JUNIOR, Gil; WERNER, Ralf; MELLO, Maricilda P. deAndrogens are responsible for the development and maintenance of male sex characteristics. Dysfunctions in androgen action due to mutations in the androgen receptor gene (AR) can lead to androgen insensitivity syndrome (AIS) that can be classified as mild (MAIS), partial (PAIS), or complete (CAIS). We have analyzed functional effects of p.Ser760Thr, p.Leu831Phe, p.Ile899Phe, p.Leu769Val, and p.Pro905Arg mutations and the combination p.Gln799Glu + p.Cys807Phe that were identified in patients with PAIS or CAIS. The p.Leu769Val and p.Pro905Arg mutations showed complete disruption of AR action under physiological hormone concentrations; however, they differed in high DHT concentrations especially in the N/C terminal interaction assay. Mutations p.Ser760Thr, p.Leu831Phe, p.Ile899Phe presented transactivation activities higher than 20% of the wild type in physiological hormone concentrations and increased with higher DHT concentrations. However, each one showed a different profile in the N/C interaction assay. When p.Gln799Glu and p.Cys807Phe were analyzed in combination, transactivation activities <10% in physiologic hormone conditions indicated an association with a CAIS phenotype. We conclude that the functional analysis elucidated the role of mutant ARs, giving clues for the molecular mechanisms associated with different clinical AIS manifestations. Differences in hormone-dependent profiles may provide a basis for the response to treatment in each particular case. (C) 2017 S. Karger AG, Basel
- Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child(2017) FRAGOSO, Maria Candida Barisson Villares; ALBUQUERQUE, Edoarda Vasco de Albuquerque; CARDOSO, Ana Luiza de Almeida; ROSA, Paula Waki Lopes da; PAULO, Rodrigo Bomeny de; SCHIMIZU, Maria Heloisa Massola; SEGURO, Antonio Carlos; PASSARELLI, Marisa; KOEHLER, Katrin; HUEBNER, Angela; ALMEIDA, Madson Q.; LATRONICO, Ana Claudia; ARNHOLD, Ivo Jorge Prado; MENDONCA, Berenice BilharinhoIntroduction: Triple A syndrome (AAAS) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and progressive neurodegeneration. Increased oxidative stress, demonstrated in patients' fibroblasts in vitro, may be a central disease mechanism. N-acetylcysteine protects renal function in patients with kidney injuries associated with increased oxidative stress and improves viability of AAAS-knockdown adrenal cells in vitro. Patient and Results: A boy diagnosed with AAAS presented with short stature and increased oxidative stress in vivo assessed by increased thiobarbituric acid reactive substances (TBARS), which are markers of lipid peroxidation, and by the susceptibility of LDL to oxidation and the capacity of HDL to prevent it. A homozygous missense germline mutation (c.523G>T, p.Val175Phe) in AAAS was identified. N-acetylcysteine (600 mg orally, twice daily) decreased oxidative stress but did not change the patient's growth pattern. Conclusions: An increase in oxidative stress is reported for the first time in vivo in an AAAS patient. N-acetylcysteine was capable of decreasing TBARS levels, reducing the susceptibility of LDL to oxidation and improving the antioxidant role of HDL. The long-term effect of antioxidant treatment should be evaluated to determine the real benefit for the prevention of the degenerative process in AAAS. (C) 2017 S. Karger AG, Basel
- Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations(2016) DUSATKOVA, Petra; PFAEFFLE, Roland; BROWN, Milton R.; AKULEVICH, Natallia; ARNHOLD, Ivo J. P.; KALINA, Maria A.; KOT, Karolina; KRZISNIK, Ciril; LEMOS, Manuel C.; MALIKOVA, Jana; NAVARDAUSKAITE, Ruta; OBERMANNOVA, Barbora; PRIBILINCOVA, Zuzana; SALLAI, Agnes; STIPANCIC, Gordana; VERKAUSKIENE, Rasa; CINEK, Ondrej; BLUM, Werner F.; PARKS, John S.; AUSTERLITZ, Frederic; LEBL, JanTwo variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations - a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants - c. [301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising similar to 101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients similar to 13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.
conferenceObject Novel Variants in the POU1F1 Beta Isoform Are Associated with Isolated Growth Hormone Deficiency and Combined Pituitary Hormone Deficiency(2018) HOPPMANN, Julia; ROCKSTROH-LIPPOLD, Denise; GERGICS, Peter; NAKAGUMA, Marilena; CARVALHO, Luciani Renata Silveira; PFAEFFLE, Heike; JAMRA, Rami Abou; JORGE, Alexander; GUO, Michael H.; DAUBER, Andrew; KELLER, Eberhard; CAMPER, Sally A.; ARNHOLD, Ivo J. P.; PFAEFFLE, Roland