Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH)

Koika, Vasiliki; Varnavas, Petros; Valavani, Helen; Sidis, Yisrael; Plummer, Lacey; Dwyer, Andrew A.; Quinton, Richard; Kanaka-Gantenbein, Christine; Pitteloud, Nelly; Sertedaki, Amalia; Dacou-Voutetakis, Catherine; Georgopoulos, Neoklis A.

doi:10.1016/j.gene.2012.12.041

Cited by 20 publications

(13 citation statements)

References 23 publications

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“…These could include evaluation of mutant signaling activity and expression levels. However, such assays for FGFR1 are highly laborious and the degree of in vitro functional impairment is not always correlated with phenotypic presentation (24,37). Nevertheless, for the mutations identified in the present study, there is substantial evidence for their pathogenicity resulting from structure-based and sequence-based prediction methods and from the absence of these variants in normal ethnicmatched controls.…”

Section: Discussionmentioning

confidence: 79%

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

Gonçalves

Bastos

Pignatelli

et al. 2015

Fertility and Sterility

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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.)

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Section: Discussionmentioning

confidence: 79%

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

Gonçalves

Bastos

Pignatelli

et al. 2015

Fertility and Sterility

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“…The highest molecular weight band (140 kDa), resistant to endoglycosidase H (EndoH) digestion, represents the mature form of FGFR1 (Fig. S5D) (Koika et al, 2013). Although total FGFR1 levels were rescued by GSK2606414 treatment (Fig.…”

Section: Fgfr1 Protein Levels Are Reduced In Vitro and In Vivo Due Tomentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

Moreau

Shi

O׳Reilly

et al. 2017

Mechanisms of Development

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Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

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“…In view of her family history, deafness and dental agenesis suggestive of autosomal KS [2, 6, 21, 25], FGFR1 gene analysis was performed revealing a recurrent heterozygous R254W missense mutation that has previously been shown to be loss-of-function in vitro [36]. …”

Section: Case Reportsmentioning

confidence: 99%

Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life

Sarfati

Bouvattier

Bry-Gauillard

et al. 2015

Orphanet J Rare Dis

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Kallmann syndrome (KS) patients carrying FGFR1 mutations can transmit the disorder to their offspring as can asymptomatic female carriers of mutations in KAL1. We describe for the first time two cases in which KS was suspected during fetal life because of the family context and malformation detection by fetal ultrasound: syndactyly or unilateral renal agenesis in subjects with respectively FGFR1 and KAL1 mutations. In relevant family history, ultrasound monitoring can detect KS associated signs before birth and thus enable neonatal diagnosis and early management. These observations also underline the importance of genetic counselling for patients who may transmit KS to their offspring.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0287-9) contains supplementary material, which is available to authorized users.

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Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH)

Cited by 20 publications

References 23 publications

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

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

Gestational stress induces the unfolded protein response, resulting in heart defects

Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life

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