期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 108, 期 8, 页码 1526-1539出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2021.06.013
关键词
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资金
- National Institutes of Health [R01HD097096, R01GM129123]
- Japan Society for Promotion of Science
- Sao Paulo Research Foundation (FAPESP) [2013/03236-5]
- Pfizer
- Argentinean National Agency of Scientific and Technical Promotion [PICT 2016-2913, PICT 2017-0002]
This study identified new variants that affect transcription and splicing of the POU1F1 gene, which may lead to pituitary hormone deficiency. The research underscores the importance of evaluating the impact of splicing on variants for interpreting unknown significance variants in POU1F1.
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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