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Title: High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency
Authors: GERGICS, PeterSMITH, CathyBANDO, HironoriJORGE, Alexander A. L.ROCKSTROH-LIPPOLD, DeniseVISHNOPOLSKA, Sebastian A.CASTINETTI, FredericMAKSUTOVA, MariamCARVALHO, Luciani Renata SilveiraHOPPMANN, JuliaMAYER, Julian MartinezALBAREL, FrederiqueBRASLAVSKY, DeboraKESELMAN, AnaBERGADA, IgnacioMARTI, Marcelo A.SAVEANU, AlexandruBARLIER, AnneJAMRA, Rami AbouGUO, Michael H.DAUBER, AndrewNAKAGUMA, MarilenaMENDONCA, Berenice B.JAYAKODY, Sajini N.OZEL, A. BilgeFANG, QingMA, QianyiLI, Jun Z.BRUE, ThierryMILLAN, Maria Ines PerezARNHOLD, Ivo J. P.PFAEFFLE, RolandKITZMAN, Jacob O.CAMPER, Sally A.
Citation: AMERICAN JOURNAL OF HUMAN GENETICS, v.108, n.8, p.1526-1539, 2021
Abstract: 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.
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Artigos e Materiais de Revistas Científicas - FM/MCM
Departamento de Clínica Médica - FM/MCM

Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - LIM/25
LIM/25 - Laboratório de Endocrinologia Celular e Molecular

Artigos e Materiais de Revistas Científicas - LIM/42
LIM/42 - Laboratório de Hormônios e Genética Molecular

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