FGFR1 – Kallmann Syndrome

Fibroblast growth factor receptor 1 (FGFR1) is a transmembrane tyrosine kinase that mediates FGF ligand–receptor signalling essential for development of gonadotropin-releasing hormone neurons and olfactory structures. Heterozygous loss-of-function variants in FGFR1 underlie an autosomal dominant form of Kallmann syndrome (Kallmann Syndrome) characterised by hypogonadotropic hypogonadism and anosmia. The clinical validity of this gene–disease relationship is supported by decades of case reports, multiple unrelated kindreds, segregation data, and experimental models.

Inheritance is autosomal dominant with variable penetrance. A three-generation kindred with reversible hypogonadotropic hypogonadism, delayed puberty, and isolated anosmia harboured the same FGFR1 stop-gain variant c.1864C>T (p.Arg622Ter) ([PMID:15613419]). Segregation of this variant with affected status in the proband, his mother, and his grandfather (delayed puberty and anosmia, respectively) demonstrates familial transmission and variable expressivity.

In multi-patient studies, FGFR1 variants are detected in ~10% of Kallmann syndrome cohorts. In a screen of 141 unrelated patients, 17 heterozygous FGFR1 sequence variants—including 10 missense, 2 nonsense, a frameshift, and 2 splice-site changes—were identified, confirming a broad variant spectrum affecting the tyrosine kinase, immunoglobulin, and splice regions ([PMID:17154279]). Recurrent stop-gain and missense alleles have not been observed as founder mutations, underscoring locus heterogeneity.

Functional studies implicate haploinsufficiency and dominant-negative effects as pathogenic mechanisms. Knock-down of fgfr1 in zebrafish phenocopies fgf8 loss at the midbrain–hindbrain boundary, and fgfr1 deficiency impairs FGF8 signalling in vivo ([PMID:15221377]). In vitro, the FGFR1 p.Trp289Ter variant is secreted and interferes with wild-type receptor–mediated ERK1/2 phosphorylation, demonstrating dominant-negative activity ([PMID:28411082]).

No conflicting evidence disputes FGFR1’s role in Kallmann syndrome, and the association has been replicated over >20 years. Additional modifier genes may influence phenotypic variability, but the core causal link is robust.

Key Take-home: Heterozygous FGFR1 loss-of-function variants reliably diagnose autosomal dominant Kallmann syndrome and guide endocrine and genetic counselling.

References

• The Journal of clinical endocrinology and metabolism • 2005 • Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. PMID:15613419
• Human mutation • 2007 • Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis. PMID:17154279
• Development genes and evolution • 2004 • Zebrafish fgfr1 is a member of the fgf8 synexpression group and is required for fgf8 signalling at the midbrain-hindbrain boundary. PMID:15221377
• Gene • 2017 • A dominant negative FGFR1 mutation identified in a Kallmann syndrome patient. PMID:28411082

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