Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 31 min ago
Peer-reviewedCC BY 4.0Frontiers in Molecular Neuroscience

ANOS1 variant and PROK2 upregulation in familial Kallmann syndrome: integrative genetic, transcriptomic, and phenotypic study

  • Katarzyna Bilińska1,2
  • Angelika Gajewska1
  • Karolina Hołub1
  • Paweł Wojciechowski3,4
  • Fernando de Castro2
  • Magdalena Pasińska1
4 affiliations
  1. 1Department of Clinical Genetics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland
  2. 2Centro de Neurociencias Cajal-CSIC, Consejo Superior de Investigaciones Científicas-CSIC, Alcalá de Henares, Spain
  3. 3Institute of Computing Science, Poznan University of Technology, Poznan, Poland
  4. 4Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
Read full textPDFDOICite

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.

Related

  1. Kallmann syndrome revealed by primary amenorrhea: Phenotypic variability and diagnostic challenges—A report of three cases
    Fatima Toulali, Rim Laaboudi, Hounaida Mahfoud +6
    Radiology case reportsPeer-reviewedCC BY-NC-NDFull textGeneral medicineEurope PMC
  2. Integrative phenotypic and transcriptomic validation of an alveolar-like macrophage model reveals early host–pathogen dynamics during Aspergillus fumigatus infection
    Jeany Söhnlein, Sascha Schäuble, Juan Prada Salcedo +9
    Frontiers in MicrobiologyPeer-reviewedCC BY 4.0Full textInfectious diseaseCrossrefEurope PMC
  3. Kallmann syndrome revealed by primary amenorrhea: Phenotypic variability and diagnostic challenges—A report of three cases
    Fatima Toulali, MD, Rim Laaboudi, MD, Hounaida Mahfoud, MD +6
    Radiology Case ReportsPeer-reviewedCC BY-NC-NDFull textObstetrics, gynaecology & paediatricsDOAJEurope PMCPMC
  4. Transdiagnostic Functional Brain Alterations Across Familial and Phenotypic Risk Samples: A Meta-Analysis
    Z. B. Millman, D. Burdinski, J. Rodriguez +4
    medRxivPreprintAll rights reservedFull textPsychiatry & mental healthmedRxiv
  5. Familial Congenital Hypothyroidism due to Compound Heterozygous Variants in the TPO Gene: Neonatal Diagnosis, Phenotypic Variability, and Lessons From Long-Term Follow-Up in Three Brothers.
    Mody Diop, Roosler Billy Telcide, Narcisse Elenga
    Case reports in geneticsPeer-reviewedCC BYFull textEndocrinology & metabolismEurope PMCPMC

Cite

BibTeXRIS
BibTeX
@article{bilinska2026anos1,
  title = {{ANOS1 variant and PROK2 upregulation in familial Kallmann syndrome: integrative genetic, transcriptomic, and phenotypic study}},
  author = {Katarzyna Bilińska and Angelika Gajewska and Karolina Hołub and Paweł Wojciechowski and Fernando de Castro and Magdalena Pasińska},
  journal = {Frontiers in Molecular Neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnmol.2026.1960672},
  url = {https://doi.org/10.3389/fnmol.2026.1960672},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - ANOS1 variant and PROK2 upregulation in familial Kallmann syndrome: integrative genetic, transcriptomic, and phenotypic study
AU  - Katarzyna Bilińska
AU  - Angelika Gajewska
AU  - Karolina Hołub
AU  - Paweł Wojciechowski
AU  - Fernando de Castro
AU  - Magdalena Pasińska
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Molecular Neuroscience
DO  - 10.3389/fnmol.2026.1960672
UR  - https://doi.org/10.3389/fnmol.2026.1960672
AB  - 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.
SN  - 1662-5099
ER  -