ANOS1 variant and PROK2 upregulation in familial Kallmann syndrome: integrative genetic, transcriptomic, and phenotypic study
Year: 2026
Type: article
Study design: Case Report
Abstract: Kallmann syndrome (KS) arises from impaired development of the olfactory–GnRH neuronal system, yet the molecular consequences of individual gene defects remain poorly defined. In particular, the link between primary genetic variants and downstream transcriptional changes affecting neurodevelopmental pathways remains poorly understood. In the present study, we analyzed a Polish family with X-linked KS. We identified a hemizygous ANOS1 variant (c.452G > C; p.Cys151Ser) in two affected brothers presenting with hypogonadotropic hypogonadism and olfactory impairment. The identified ANOS1 variant remains classified as a variant of uncertain significance (VUS); however, its segregation with the KS phenotype and substitution of a highly conserved cysteine residue within the WAP domain supports its potential functional relevance and further investigation. The minigene assay did not reveal detectable effects on ANOS1 pre-mRNA splicing, while direct transcript analysis was limited by very low ANOS1 expression in peripheral blood. Whole-blood RNA sequencing revealed significant upregulation of PROK2 in the affected individuals, and qRT-PCR showed concordant upregulation in both patients. No coding or splice-site variants or detectable exon-usage alterations were identified in PROK2 . Given the complementary roles of ANOS1 and PROK2 in olfactory system development and GnRH neuron migration, and previous evidence linking anosmin-1 to PK2/PROKR2 signaling, these findings suggest that ANOS1 -associated dysfunction may be accompanied by secondary changes in functionally related molecular pathways, although this interpretation requires validation in appropriate experimental models.
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223171702