<em>Lhx9</em> is a candidate premature ovarian insufficiency gene in humans and mice — ASN Events
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Lhx9 is a candidate premature ovarian insufficiency gene in humans and mice (#492)

Bridget J Fellows 1 , Katie Walker 1 , Louise S Bicknell 1 , Megan J Wilson 1
  1. University of Otago, Dunedin, New Zealand

Background

Precise temporospatial gene expression is essential for normal mammalian development. Transcription factors play crucial roles in developmental pathways and dysregulation can lead to developmental disorders, adult disease, or cancer.

LIM homeobox 9 (Lhx9) encodes a transcription factor important in development of the limbs, heart, and central nervous system, and essential in gonadal development. Lhx9 continues to be expressed by several cell types throughout the adult ovary. Lhx9 knockout (Lhx9-/-) causes gonadal agenesis in mice, whilst Lhx9 heterozygous (Lhx9+/-) females have decreased ovarian reserve and are subfertile. Human LHX9 variants have been reported in individuals with premature ovarian insufficiency and male-to-female sex reversal, but the mechanisms by which LHX9 contributes are unknown.

Methods

Spatial transcriptomics was performed on Lhx9 wildtype (Lhx9+/+) and Lhx9+/- adult mouse ovaries to explore gene expression alterations and corresponding morphological changes.

Novel germline variants in LHX9, associated with disorders of sex development or female infertility, were identified from the UK Biobank database. Candidate variants were prioritised using in silico protein modelling, and we conducted in vitro cell culture studies to investigate the consequences on LHX9 protein stability and function.

Results

Spatial transcriptomics revealed altered expression of DNA repair genes, including mismatch repair genes Mlh1 and Msh2, together with homologous recombination gene Palb2, in granulosa and theca cells in the Lhx9+/- adult ovary, suggesting activation of DNA damage response pathways.

LHX9 missense variants were strongly associated with female infertility in UK Biobank participants (OR=21.9, p-value=0.0001). One variant, LHX9 p.P292L, alters a highly conserved residue within the DNA binding domain of LHX9 and reduces protein stability in vitro (p-value<0.0001).

Conclusion

Molecular and functional studies in both human and mice models support a role for LHX9 in maintaining ovarian homeostasis and genomic integrity, with dysregulation of DNA repair pathways representing a potential mechanism contributing to premature ovarian insufficiency.