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

Abstract : 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.
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https://hal-amu.archives-ouvertes.fr/hal-03293410
Contributor : Valérie Gall <>
Submitted on : Wednesday, July 21, 2021 - 8:49:57 AM
Last modification on : Tuesday, August 31, 2021 - 4:19:17 PM

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Peter Gergics, Cathy Smith, Hironori Bando, Alexander A.L. Jorge, Denise Rockstroh-Lippold, et al.. High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency. American Journal of Human Genetics, Elsevier (Cell Press), 2021, 108 (8), pp.1526-1539. ⟨10.1016/j.ajhg.2021.06.013⟩. ⟨hal-03293410⟩

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