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

Autor:	Gergics P; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Smith C; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218, USA., Bando H; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Jorge AAL; Genetic Endocrinology Unit (LIM25), Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brazil., Rockstroh-Lippold D; Department of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany., Vishnopolska SA; Instituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Castinetti F; Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France., Maksutova M; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Carvalho LRS; Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil., Hoppmann J; Department of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany., Martínez Mayer J; Instituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Albarel F; Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France., Braslavsky D; Centro de Investigaciones Endocrinológicas 'Dr. César Bergadá,' FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Keselman A; Centro de Investigaciones Endocrinológicas 'Dr. César Bergadá,' FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Bergadá I; Centro de Investigaciones Endocrinológicas 'Dr. César Bergadá,' FEI - CONICET - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Martí MA; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales CONICET, Pabellòn 2 de Ciudad Universitaria, Ciudad de Buenos Aires, CABA C1428EHA, Argentina., Saveanu A; Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Laboratory of Molecular Biology, Marseille 13385, France., Barlier A; Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Laboratory of Molecular Biology, Marseille 13385, France., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany., Guo MH; Division of Endocrinology, Boston Children's Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Dauber A; Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Nakaguma M; Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil., Mendonca BB; Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil., Jayakody SN; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Ozel AB; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Fang Q; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Ma Q; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Li JZ; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA., Brue T; Aix Marseille University, AP-HM, INSERM, Marseille Medical Genetics, Marmara Institute, La Conception Hospital, Department of Endocrinology, Marseille 13005, France., Pérez Millán MI; Instituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina., Arnhold IJP; Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil., Pfaeffle R; Department of Women's and Child Health, Division of Pediatric Endocrinology, University Hospital Leipzig, Leipzig 04103, Germany; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany., Kitzman JO; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218, USA. Electronic address: kitzmanj@umich.edu., Camper SA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA. Electronic address: scamper@med.umich.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Aug 05; Vol. 108 (8), pp. 1526-1539. Date of Electronic Publication: 2021 Jul 15.
DOI:	10.1016/j.ajhg.2021.06.013
Abstrakt:	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. (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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