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FGF8 and FGFR1 mutations

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  • OMIM 600483

  • Located at chromosome 10q24

  • Encodes fibroblast growth factor 8 (originally called androgen-induced growth factor)

  • FGF8 is an FGFR1 ligand involved in the developing olfactory and reproductive systems.

  • FGF8 comprises 6 exons, including 4 alternative first exons (1A, 1B, 1C and 1D) and giving rise to 5 alternative isoforms (A, B, E, F and G).

  • The longest corresponding mRNA (NM_033163.3) encodes a 244 amino acid protein (F isoform). Other isoforms include:

    • A isoform, NM_033165.3: 204 amino acids

    • B isoform, NM_006119.4: 215 amino acids

    • E isoform, NM_033164.3: 233 amino acids

    • G isoform NM_001206389.1: 140 amino acids

Human genetics

  • Congenital hypogonadotropic hypogonadism associated with FGF8 mutations is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity (Falardeau, Chung et al. 2008) or in an oligogenic manner (Sykiotis, Plummer et al. 2010).

  • Mutations in FGF8 have been associated with:

    • Congenital hypogonadotropic hypogonadism with or without anosmia (Falardeau, Chung et al. 2008)

    • Holoprosencephaly without evidence for hypogonadism (Arauz, Solomon et al. 2010)

    • Recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction (McCabe, Gaston-Massuet et al. 2011)

    • Combined pituitary hormone deficiency without midline defects (Raivio, Avbelj et al. 2012)

    • Non-syndromic cleft lip/palate (Riley, Mansilla et al. 2007).


Animal models


  • Mice homozygous for a hypomorphic Fgf8 allele lack GnRH neurons in the hypothalamus (Chung, Moyle et al. 2008).

  • Heterozygous mice show substantial decreases in the number of GnRH neurons and in hypothalamic GnRH peptide concentration (Falardeau, Chung et al. 2008).




Arauz, R. F., B. D. Solomon, et al. (2010). "A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans." Mol Syndromol 1(2): 59-66.

Chung, W. C., S. S. Moyle, et al. (2008). "Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons." Endocrinology 149(10): 4997-5003.

Falardeau, J., W. C. Chung, et al. (2008). "Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice." J Clin Invest 118(8): 2822-2831.

McCabe, M. J., C. Gaston-Massuet, et al. (2011). "Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction." J Clin Endocrinol Metab 96(10): E1709-1718.

Raivio, T., M. Avbelj, et al. (2012). "Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia." J Clin Endocrinol Metab 97(4): E694-699.

Riley, B. M., M. A. Mansilla, et al. (2007). "Impaired FGF signaling contributes to cleft lip and palate." Proc Natl Acad Sci U S A 104(11): 4512-4517.

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.