POU6F2 mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression
Cho, H.-J.; Gurbuz, F.; Stamou, M.; Kotan, L. D.; Farmer, S. M.; Can, S.; Tompkins, M. F.; Mammadova, J.; Altincik, S. A.; Gokce, C.; Catli, G.; Bugrul, F.; Bartlett, K.; Turan, I.; Balasubramanian, R.; Yuksel, B.; Seminara, S.; Wray, S.; Topaloglu, A. K.
Show abstract
Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent pubertal development and infertility, often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2. POU6F2 encodes two distinct isoforms. In mouse, pituitary and gonads expressed both isoforms, but only isoform1 was detected in GnRH cells. Although the function of isoform2 is well known, using bioinformatics and cells assays on a human-derived GnRH cell line, we demonstrate isoform1 can also act as a transcriptional regulator, decreasing GNRH1 expression. The impact of two POU6F2 variants (MT1 and MT2) was then examined. MT1, but not MT2, reduced transcriptional activity of either isoform, preventing Hes5 promoter activation by isoform2 and repression of GnRH transcripts by isoform1. GnRH transcription increases as the cells migrate into the brain. Augmentation earlier can disrupt normal GnRH cell migration, consistent with POU6F2 variants contributing to IHH pathogenesis.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Generation and mutational analysis of a transgenic mouse model of human SRY 95%
- Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay 93%
- 5’ splice site GC>GT variants differ from GT>GC variants in terms of their functionality and pathogenicity 92%
Similar papers in this journal
Similar papers in this journal
- Deletion of FUNDC2 and CMC4 on chromosome Xq28 is sufficient to cause hypergonadotropic hypogonadism in men 95%
- Evolutionary Perspective And Expression Analysis Of Intronless Genes Highlight The Conservation On Their Regulatory Role 93%
- Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis 92%
Similar papers in this journal
- Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice 94%
- Clusters of deep intronic RbFox motifs embedded in large assembly of splicing regulators sequences regulate alternative splicing 93%
- From paleness to albinism: Contribution of OCA2 exon 10 skipping to hypopigmentation 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.