ESPE2024 Free Communications Growth and Syndromes (6 abstracts)
Gene expression of monosomy × during human development reveals potential mechanisms in Turner syndrome
Jenifer Suntharalingham 1 , Ignacio Del Valle 1 , Federica Buonocore 1 , Sinead McGlacken-Byrne 1 , Tony Brooks 2 , Olumide Ogunbiyi 3,1,4 , Danielle Liptrot 1 , Nathan Dunton 2 , Gaganjit Madhan 2 , Kate Metcalfe 1 , Lydia Nel 1 , Abigail Marshall 1 , Miho Ishida 1 , Neil Sebire 3,1,4 , Gudrun Moore 1 , Berta Crespo 1 , Nita Solanky 1 , Gerard Conway 5 & John Achermann 1
1UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 2UCL Zayed Centre for Research into Rare Disease in Children, London, United Kingdom. 3Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 4NIHR Great Ormond Street Biomedical Research Centre, London, United Kingdom. 5University College London Hospital, London, United Kingdom
Background: Monosomy × (45,X) is associated with Turner syndrome (TS) and pregnancy loss; however, the underlying mechanisms remain unclear. Girls and young women with TS/45,X can present with diverse clinical features and at different ages, including early postnatal life, suggesting that at least some mechanisms may be defined during early fetal development.
Aims: To explore transcriptomic expression profiles in key monosomy × tissues during development and to identify potential genes that drive the clinical features of TS.
Methods: Bulk RNA sequencing was undertaken in 45,X tissues (n = 20) between 11 weeks post conception (wpc) and 15wpc, and compared with aged matched 46,XX (n = 20) and 46,XY (n = 20) controls. Pancreas, liver, kidney, skin and a mixed group (brain, heart, lung, spleen) were considered. A separate subgroup of 45,X placenta was also studied with matched controls (total n = 18). DESeq2 and pathway analysis was used to investigate differential gene expression analysis of individual tissues related to karyotype, and findings validated using qRT-PCR and immunohistochemistry (IHC).
Results: 1) Many pseudoautosomal region 1 (PAR1) genes showed consistently lower gene expression in monosomy × tissues (e.g., SLC25A6, AKAP17A, GTPBP6, ZBED1). Lower expression of several key genes escaping × inactivation (e.g., KDM5C and KDM6A) was also seen, as well as genes regulating lipids (LDLR), blood pressure (AGTR2), and thoracic/ascending aortic aneurysm (e.g., aortic remodelling (collagen genes) and Marfan syndrome (FBN1)). 2) Interestingly, higher expression of an autosomal, long non-coding RNA located on chromosome 12 (OVCH1-AS1) was consistently detected across all 45,X tissue groups studied. OVCH1-AS1 is found only in humans/primates, and its biological role is currently unknown. 3) In the placental subgroup analysis, two genes were found to have placental-specific lower expression in 45,X tissue (CSF2RA, AADACL3). CSF2RA is a PAR1 gene that encodes a subunit of the GM-CSF receptor. Detailed IHC and single cell RNA-sequencing showed CSFR2A /GM-CSFR alpha expression in the (syncytio)trophoblastic layer and haematopoietic cells. CSF2RA /GM-CSFR alpha was disrupted in 45,X placenta undergoing villus degeneration, suggesting a role in placental immune dysregulation.
Conclusion: To our knowledge, this is the first detailed transcriptomic study of human monosomy × in fetal development, and in tissues directly associated with some of the phenotypic features of TS. These findings provide novel insights into the biological consequences of a 45,X karyotype and could lead to potential therapeutic strategies to improve clinical care for women and girls with Turner syndrome.
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