Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform.
OBJECTIVE
To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH).


METHODS
Cross-sectional study.


METHODS
Multicentric.


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


METHODS
None.


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


RESULTS
Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*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.


CONCLUSIONS
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.
CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Catarina
C
Gonçalves
Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
Margarida
M
Bastos
Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de São João e Faculdade de Medicina do Porto, Porto, Portugal.
Duarte
D
Pignatelli
Serviço de Pediatria Médica, Centro Hospitalar do Porto, Porto, Portugal.
Teresa
T
Borges
Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Lisbon, Portugal.
José M
JM
Aragüés
Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Curry Cabral, Lisbon, Portugal.
Fernando
F
Fonseca
Serviço de Endocrinologia e Diabetes, Hospital Garcia de Orta, Almada, Portugal.
Bernardo D
BD
Pereira
CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Sílvia
S
Socorro
CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. Electronic address: mclemos@fcsaude.ubi.pt.
Manuel C
MC
Lemos
D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D003198:Computer Simulation; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017436:Kallmann Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D011487:Protein Conformation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D055815:Young Adult
C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
FGFR1; Hypogonadotropic hypogonadism; KAL2; Kallmann syndrome; genetics