High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

BANDO, HIRONORI; VISHNOPOLSKA, SEBASTIAN A.; CARVALHO, LUCIANI RENATA SILVEIRA; ALBAREL, FRÉDÉRIQUE; BERGADÁ, IGNACIO; BARLIER, ANNE; DAUBER, ANDREW; JAYAKODY, SAJINI N.; MA, QIANYI; PÉREZ MILLÁN, MARÍA INES; KITZMAN, JACOB O.; GERGICS, PETER; JORGE, ALEXANDER A.L.; CASTINETTI, FREDERIC; HOPPMANN, JULIA; BRASLAVSKY, DEBORA; MARTÍ, MARCELO A.; ABOU JAMRA, RAMI; NAKAGUMA, MARILENA; OZEL, A. BILGE; LI, JUN Z.; ARNHOLD, IVO J.P.; CAMPER, SALLY A.; SMITH, CATHY; ROCKSTROH-LIPPOLD, DENISE; MAKSUTOVA, MARIAM; MARTÍNEZ MAYER, JULIÁN; KESELMAN, ANA; SAVEANU, ALEXANDRU; GUO, MICHAEL H.; MENDONCA, BERENICE B.; FANG, QING; BRUE, THIERRY; PFAEFFLE, ROLAND

AMERICAN JOURNAL OF HUMAN GENETICS

CELL PRESS

Año: 2021 vol. 108 p. 1526 - 1539

0002-9297

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.