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FGF8 and FGFR1 mutations

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  • OMIM 136350

  • Located at chromosome 8p11.2

  • Encodes the fibroblast growth factor receptor 1, a cell surface receptor of the tyrosine kinase family.

  • FGFR1 comprises 18 exons and the corresponding mRNA (NM_023110.2) encodes an 820 amino acid protein, FGFR1.

Human genetics

  • Mutations in FGFR1 are found in approximately 10% of patients with congenital hypogonadotropic hypogonadism (CHH), and have been associated with both Kallmann syndrome (Dode, Levilliers et al. 2003) and normosmic CHH (Pitteloud, Acierno et al. 2006). More than 120 different point mutations have been identified. About 70% of these mutations are missense mutations.

  • CHH associated with mutations in FGFR1 is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity (Dode, Levilliers et al. 2003), or in an oligogenic manner (Sykiotis, Plummer et al. 2010).

  • The mutations are distributed throughout the gene (Miraoui, Dwyer et al. 2011).

Six different missense mutations of FGFR1, in the homozygous or heterozygous state, have been associated with Hartsfield syndrome (holoprosencephaly and ectrodactyly), but it is still unclear whether all these patients also have CHH (Simonis, Migeotte et al., 2013).


Animal models

  • Mice homozygous for a hypomorphic Fgfr1 allele have fewer GnRH cells in the preoptic/hypothalamic region of the brain (Chung, Moyle and Tsai 2008)




Dode, C., J. Levilliers, et al. (2003). "Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome." Nat Genet 33(4): 463-465.

Miraoui, H., A. Dwyer, et al. (2011). "Role of fibroblast growth factor (FGF) signaling in the neuroendocrine control of human reproduction." Mol Cell Endocrinol 346(1-2): 37-43.

Pitteloud, N., J. S. Acierno, Jr., et al. (2006). "Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism." Proc Natl Acad Sci U S A 103(16): 6281-6286.

Sykiotis, G. P., L. Plummer, et al. (2010). "Oligogenic basis of isolated gonadotropin-releasing hormone deficiency." Proc Natl Acad Sci U S A 107(34): 15140-15144.