Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.

Abstract

BACKGROUND:

Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described.

RESULTS:

One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations.

CONCLUSION:

KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.

• Authors: Nelly Pitteloud, Astrid Meysing, Richard Quinton, James S Acierno Jr, Andrew A Dwyer, Lacey Plummer, Eric Fliers, Paul Boepple, Frances Hayes, Stephanie Seminara, Viriginia A Hughes, Jinghong Ma, Pierre Bouloux, Moosa Mohammadi, William F Crowley Jr
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 254-255 Pg. 60-9 (Jul 25 2006) ISSN: 0303-7207 [Print] Ireland
• PMID: 16764984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Adolescent
• Child
• Cleft Palate (genetics)
• Cohort Studies
• DNA Mutational Analysis
• Female
• Gene Frequency
• Genetic Variation
• Humans
• Hypogonadism (genetics)
• Kallmann Syndrome (genetics)
• Male
• Models, Molecular
• Mutation
• Olfaction Disorders (genetics)
• Pedigree
• Phenotype
• Puberty, Delayed (genetics)
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, physiology)
• Reproduction (genetics, physiology)