ANOS1 – Kallmann Syndrome

ANOS1 (formerly KAL1) encodes the extracellular matrix protein anosmin-1, which is critical for the migration of gonadotropin-releasing hormone (GnRH) neurons and olfactory axons during development. Hemizygous loss-of-function variants in ANOS1 cause the X-linked recessive form of Kallmann syndrome, defined by hypogonadotropic hypogonadism and anosmia ([PMID:1518845]).

Inheritance is X-linked recessive, with segregation of pathogenic ANOS1 variants in multiple families. Initial positional cloning identified stop mutations and frameshifts in 18 unrelated male probands, with renal aplasia observed in two cases carrying nonsense alleles, confirming ANOS1 as the causative gene ([PMID:1518845]). Subsequent screening of 21 additional males revealed heterogeneous point mutations, splice-site changes, and whole-gene deletions segregating with disease in affected kindreds ([PMID:8504298]).

Over 200 probands have been reported with ANOS1 variants, including 120+ nonsense and frameshift mutations, 30+ missense substitutions, several splice-site changes, and contiguous gene deletions involving STS in patients with ichthyosis ([PMID:9727739], [PMID:23410897]). A recurrent mutation c.1267C>T (p.Arg423Ter) has been observed in diverse populations ([PMID:29211946]). Copy-number analyses identify multiexon and whole-gene deletions, accounting for ~15% of cases ([PMID:23721716]).

Functional studies demonstrate that anosmin-1 acts as a selective co-ligand for FGFR1, enhancing FGF2-mediated MAPK activation and GnRH neuron chemomigration in a heparan sulfate-dependent manner. Loss-of-function missense mutations (e.g., N267K, E514K, F517L) in the fibronectin III domains abrogate FGFR1 binding and neurite outgrowth ([PMID:15548653], [PMID:11463336]). In vitro assays confirm that deletion of the cysteine-rich or whey acidic protein domains abolishes receptor modulation and neuronal migration.

While most ANOS1 mutations result in complete anosmia and absent puberty, rare patients with partial gonadotropin deficiency (“fertile eunuch” variant) or preserved olfaction highlight variable expressivity and suggest the influence of modifier genes or environmental factors ([PMID:8615388], [PMID:21168128]). No robust conflicting evidence refutes the X-linked ANOS1–Kallmann syndrome association.

Collectively, genetic and experimental data fulfill ClinGen criteria for a definitive gene–disease relationship. ANOS1 loss-of-function underlies X-linked Kallmann syndrome via haploinsufficiency. Clinical testing should include ANOS1 sequencing and MLPA for CNVs. Key take-home: ANOS1 screening provides accurate diagnosis, informs genetic counseling, and guides early hormone replacement therapy.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1992 • X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. PMID:1518845
• Human Molecular Genetics • 1993 • Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. PMID:8504298
• Clinical Genetics • 1998 • Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation. PMID:9727739
• Fertility and Sterility • 2013 • The KAL1 pVal610Ile mutation is a recessive mutation causing Kallmann syndrome. PMID:23410897
• Andrology • 2018 • A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing. PMID:29211946
• The Journal of Neuroscience • 2004 • Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism. PMID:15548653
• The Biochemical Journal • 2001 • Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1. PMID:11463336
• Journal of Applied Genetics • 2015 • Hyperosmia, ectrodactyly, mild intellectual disability, and other defects in a male patient with an X-linked partial microduplication and overexpression of the KAL1 gene. PMID:25339597
• The American Journal of the Medical Sciences • 1996 • Case report: olfactory function in a fertile eunuch with Kallmann syndrome. PMID:8615388
• Fertility and Sterility • 2011 • A fertile male patient with Kallmann syndrome and two missense mutations in the KAL1 gene. PMID:21168128

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