ESPEYB19 1. Pituitary and Neuroendocrinology Genetics (5 abstracts)
1.6. High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency
Gergics P , Smith C , Bando H , Jorge AAL , Rockstroh-Lippold D , Vishnopolska SA , Castinetti F , Maksutova M , Carvalho LRS , Hoppmann J , Martínez Mayer J , Albarel F , Braslavsky D , Keselman A , Bergadá I , Martí MA , Saveanu A , Barlier A , Abou Jamra R , Guo MH , Dauber A , Nakaguma M , Mendonca BB , Jayakody SN , Ozel AB , Fang Q , Ma Q , Li JZ , Brue T , Pérez Millán MI , Arnhold IJP , Pfaeffle R , Kitzman JO & Camper SA
Am J Hum Genet. 2021 Aug 5;108(8):1526-1539. doi: 10.1016/j.ajhg.2021.06.013. PMID: 34270938.
Brief Summary: This study reports splice-disruptive variants in POU1F1 in 4 families with hypopituitarism and uses a high-throughput splicing reporter assay to create a comprehensive catalogue of such variants in or near exon 2 of the gene. The catalogue paves the way for identifying synonymous but splice-disruptive POU1F1 variants in additional patients with hypopituitarism, which underscores the importance of evaluating defective splicing as a disease mechanism.
Defects in POU1F1 are well-known causes of hypopituitarism (1). The gene undergoes alternative splicing, to produce the main alpha and the minor beta isoform that act as a transcriptional activator and repressor, respectively. The so far reported dominant-negative POU1F1 variants are located in domains shared by both isoforms and have been functionally tested only for the alpha isoform.
Here, the authors report 4 families with hypopituitarism and heterozygous missense variants in exon 2 of the POU1F1 beta isoform. Functional assays showed that the variants shifted splicing to the production of the beta isoform, which causes dominant-negative loss-of function by suppressing the alpha isoform. A high-throughput splicing reporter assay was used to measure the impact of 1070 single-nucleotide variants in POU1F1 exon 2 and flanking intronic regions on splicing. This approach revealed 96 splice-disrupting variants of which 14 were synonymous. Two of the synonymous variants were present in 2 additional, unrelated patients with hypopituitarism and both increased the beta isoform usage.
This study reminds us about the importance of evaluating the effects of variants, including the coding ones, on splicing. Moreover, it introduces a splicing effect catalogue of POU1F1 variants and highlights the increase of the beta isoform usage as a consequence of splice-disruptive variants in this gene.
Reference: 1. Jadhav S, Diwaker C, Lila AR, Gada JV, Kale S, Sarathi V, Thadani PM, Arya S, Patil VA, Shah NS, Bandgar TR. POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature. Pituitary 2021 Oct;24(5):657–669.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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