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
3 resultados
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conferenceObject Gene Identification in Patients with Hypopituitarism: Next Generation Exome Sequencing Experience(2014) FANG, Qing; ARNHOLD, Ivo J. P.; BENEDETTI, Anna Flavia F.; MENDONAA, Berenice Bilharinho; BRUE, Thierry; CARVALHO, Luciani R. S.; CASTINETTI, Frederic; CORREA, Fernanda de Azevedo; LI, Jun Z.; MA, Qianyi; REYNAUD, Rachel; CAMPER, Sally Ann- 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.
- 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.