WFS1 deficiency impacts GnRH neurons development through ER stress response failure

Wolfram Syndrome, a rare neurodegenerative disorder caused by biallelic mutations in the WFS1 gene, presents with endocrine and neurological features. Although hypogonadism has been described in Wolfram Syndrome, the role of WFS1 in reproductive development is not well understood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by deficient development or function of gonadotropin-releasing hormone (GnRH) neurons. While several causative genes have been identified, many CHH cases remain genetically unexplained. Using whole-exome sequencing in familial CHH cases, we identified two rare heterozygous missense variants in WFS1. Functional in vitro assays revealed reduced protein levels, activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR). In vivo studies in zebrafish and mouse embryos showed WFS1 expression in regions critical for GnRH neuron development. Knockdown of wfs1b in Tg(GnRH3: EGFP) zebrafish embryos disrupted GnRH3 neuronal architecture and downregulated isl1a, a key transcription factor for axon guidance. Our findings establish a mechanistic link between WFS1-mediated ER homeostasis, isl1a expression, and GnRH neuron development. We propose WFS1 as a novel candidate gene in CHH pathogenesis and provide in vivo evidence that ER stress and isl1a dysregulation impair the formation of GnRH neuronal network.