info:eu-repo/semantics/article
High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency
Fecha
2021-08Registro en:
Gergics, Peter; Smith, Cathy; Bando, Hironori; Jorge, Alexander A. L.; Rockstroh Lippold, Denise; et al.; High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency; Cell Press; American Journal Of Human Genetics; 108; 8; 8-2021; 1526-1539
0002-9297
CONICET Digital
CONICET
Autor
Gergics, Peter
Smith, Cathy
Bando, Hironori
Jorge, Alexander A. L.
Rockstroh Lippold, Denise
Vishnopolska, Sebastián Alexis
Castinetti, Frederic
Maksutova, Mariam
Carvalho, Luciani Renata Silveira
Hoppmann, Julia
Martínez Mayer, Julián Jorge
Albarel, Frédérique
Braslavsky, Debora Giselle
Keselman, Ana Claudia
Bergadá, Ignacio
Marti, Marcelo Adrian
Saveanu, Alexandru
Barlier, Anne
Abou Jamra, Rami
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
Pérez Millán, María Inés
Arnhold, Ivo J. P.
Pfaeffle, Roland
Kitzman, Jacob
Camper, Sally
Resumen
Pituitary hormone deficiency occurs in ∼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.