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

Abstract

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). Design: Cross-sectional study. Result(s): 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. Conclusion(s): 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. (Fertil Steril Ò 2015;104: 1261-7. Ó2015 by American Society for Reproductive Medicine.)

Novel rare variants in FGFR1 and clinical characteristics analysis in a series of congenital hypogonadotropic hypogonadism patients

“…The prevalence of FGFR1 LP variants in this CHH series was 7.3%, and in KS and nCHH subgroups, the prevalence is 9.9% and 3.9% respectively. The incidence of these variants was comparable to that in other studies 3,4,25,26,27 . While the functional study was not carried out in vitro, indirect evidence supports the deleterious impact of the 18 novel LP variants identified in this study.…”

“…The incidence of these variants was comparable to that in other studies. 3,4,25,26,27 While the functional study was not carried out in vitro, indirect evidence supports the deleterious impact of the 18 novel LP variants identified in this study. sults in an absent or disrupted protein product by transmitting an abnormal message.…”

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

“…(c) Patient previously reported by Gonçalves et al . 15 .

Figure 1 CHD7 mutations identified in patients with CHH. Arrows represent index cases, filled symbols represent affected individuals, open symbols represent unaffected individuals, squares denote men, circles denote women, oblique lines through symbols represent deceased individuals.

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“…Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leucocytes using previously described methods 13 . Patients had already been screened for mutations in the ANOS1 , FGFR1 and GNRHR genes, resulting in the discovery of three mutations in ANOS1 14 , six mutations in FGFR1 15 and six mutations in GNRHR 16 . All 50 patients were subsequently screened for mutations in the CHD7 gene by polymerase chain reaction (PCR) amplification of the coding exons and exon-intron boundaries, and bi-directional sequencing using CEQ DTCS sequencing kit (Beckman Coulter, Fullerton, CA, USA) and an automated capillary DNA sequencer (GenomeLab TM GeXP, Genetic Analysis System, Beckman Coulter).…”

Mechanisms of Central Hypogonadism

“…Mutations within ANOS1 transmit through familial X-linkage and influence early migration of GnRH neurons [ 35 ]. Conversely, mutations within FGFR1 (affecting ~12% of men with KS [ 36 ]) transmit through an autosomal dominant mode, and together with mutations in PROK1 and PROK2 (G-protein coupled receptors) influence both GnRH neuronal migration and olfactory bulb development [ 37 , 38 ]. Other genes implicated in the pathogenesis of KS include GNRHR that encodes the GnRH receptor [ 39 ], CHD7 [ 40 ] and FGF8 [ 41 ].…”