Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism Evidence for the involvement of an alternatively spliced isoform

This study identified six new FGFR1 mutations responsible for IHH and provides evidence that an alternative form of the encoded protein (isoform IIIb) can also cause this disorder.


Catarina Gonçalves, M.Sc., Margarida Bastos, M.D., Duarte Pignatelli, M.D., Ph.D., Teresa Borges, M.D., José M. Aragüés, M.D., Fernando Fonseca, M.D., Bernardo D. Pereira, M.D., Sílvia Socorro, Ph.D., Manuel C. Lemos, M.D., Ph.D.

Volume 104, Issue 5, Pages 1261-1267



To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH).


Cross-sectional study.




Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH).



Main Outcome Measure(s):

Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis.


Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient.


Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms.

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