igh-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficienc

Author(s):Show less -

Gergics, Peter ^[1] ; Smith, Cathy ^{[1, 2]} ; Bando, Hironori ^{[1, 3]} ; Jorge, Alexander A. L. ^[4] ; Rockstroh-Lippold, Denise ^{[5, 6]} ; Vishnopolska, Sebastian A. ^[7] ; Castinetti, Frederic ^[8] ; Maksutova, Mariam ^[1] ; Silveira Carvalho, Luciani Renata ^[9] ; Hoppmann, Julia ^{[5, 10]} ; Mayer, Julian Martinez ^[7] ; Albarel, Frederique ^[8] ; Braslavsky, Debora ^[11] ; Keselman, Ana ^[11] ; Bergada, Ignacio ^[11] ; Marti, Marcelo A. ^{[12, 13]} ; Saveanu, Alexandru ^[14] ; Barlier, Anne ^[14] ; Abou Jamra, Rami ^[15] ; Guo, Michael H. ^{[16, 17, 18]} ; Dauber, Andrew ^{[19, 20]} ; Nakaguma, Marilena ^[9] ; Mendonca, Berenice B. ^[9] ; Jayakody, Sajini N. ^[1] ; Ozel, A. Bilge ^[1] ; Fang, Qing ^[1] ; Ma, Qianyi ^[1] ; Li, Jun Z. ^[1] ; Brue, Thierry ^[8] ; Millan, Maria Ines Perez ^[7] ; Arnhold, Ivo J. P. ^[9] ; Pfaeffle, Roland ^{[5, 15]} ; Kitzman, Jacob O. ^{[1, 2]} ; Camper, Sally A. ^[1]

Affiliation:Show less -

^[1] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 - USA

^[2] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 - USA

^[3] Kobe Univ, Div Diabet & Endocrinol, Grad Sch Med, Kobe, Hyogo 6500017 - Japan

^[4] Univ Sao Paulo, Hosp Clin, Genet Endocrinol Unit LIM25, Div Endocrinol, Fac Med, BR-01246903 Sao Paulo - Brazil

^[5] Univ Hosp Leipzig, Dept Womens & Child Hlth, Div Pediat Endocrinol, D-04103 Leipzig - Germany

^[6] Beckman Coulter, D-47807 Krefeld - Germany

^[7] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Inst Biociencias Biotecnol & Biol Traslac, Dept Fisiol Biol Mol & Celular, CE1428EHA, Caba - Argentina

^[8] Aix Marseille Univ, La Conception Hosp, AP HM, Dept Endocrinol, Marmara Inst, INSERM, F-13005 Marseille - France

^[9] Univ Sao Paulo, Hosp Clin, Div Endocrinol, Fac Med, Lab Hormones & Mol Genet LIM 42, Dev Endocrinol Un, BR-05403900 Sao Paulo - Brazil

^[10] Univ Lubeck, Dept Paediat & Adolescent Med, Div Paediat Endocrinol & Diabet, D-23528 Lubeck - Germany

^[11] Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol Dr Cesar Bergada, FEI CONICET Div Endocrinol, CE1428EHA, Buenos Aires, Caba - Argentina

^[12] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Pabellon 2 Ciudad Univ, C1428EHA, Buenos Aires, Caba - Argentina

^[13] Consejo Nacl Invest Cient & Tecn, Inst Quim Biol, Fac Ciencias Exactas & Nat, Pabellon 2 Ciudad Univ, C1428EHA, Buenos Aires, Caba - Argentina

^[14] Aix Marseille Univ, La Conception Hosp, AP HM, Lab Mol Biol, Marmara Inst, INSERM, Marseille Med Ge, F-13385 Marseille - France

^[15] Univ Leipzig, Inst Human Genet, Med Ctr, D-04103 Leipzig - Germany

^[16] Univ Penn, Dept Neurol, Philadelphia, PA 19104 - USA

^[17] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 - USA

^[18] Harvard Med Sch, Dept Genet, Boston, MA 02115 - USA

^[19] Cincinnati Childrens Hosp Med Ctr, Cincinnati Ctr Growth Disorders, Div Endocrinol, Cincinnati, OH 45229 - USA

^[20] Childrens Natl Hosp, Div Endocrinol, Washington, DC 20012 - USA

• Document type: Journal article
• Source: American Journal of Human Genetics; v. 108, n. 8, p. 1526-1539, AUG 5 2021.
• Web of Science Citations: 4

Abstract

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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants