Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia

Trarbach, Ericka Barbosa; Costa, Elaine Maria Frade; Versiani, Beatriz R.; Castro, Margaret de; Baptista, Mónica; Garmes, Heraldo Mendes; Mendonça, Berenice Bilharinho; Latrônico, Ana Claudia

doi:10.1210/jc.2005-2793

Cited by 88 publications

(91 citation statements)

References 34 publications

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“…Our study of 50 patients with IHH identified six novel heterozygous FGFR1 mutations, including a mutation in the alternatively spliced exon 8A of this gene. The frequency of FGFR1 mutations in KS and in normosmic IHH probands was 14% (3 in 21) and 10% (3 in 29), respectively, which is consistent with results presented in other studies (6,13,14,(23)(24)(25)(26)(27).…”

Section: Discussionsupporting

confidence: 91%

“…Thus, our study provides additional evidence for a role of the FGFR1-IIIb isoform in the pathogenesis of IHH, and indicates the need to include routine sequencing of exon 8A (in addition to exon 8B) in genetic screening of both KS and normosmic IHH in populations of all ethnicities. This is important because researchers occasionally exclude exon 8A from their genetic analysis (23,33), leading to the risk of missed mutations. It remains to be clarified whether the relative rarity of observed exon 8A mutations is due to lack of appropriate screening of this exon in the DNA sequence analysis, to the absence of phenotypic expression of most mutations in this exon, or to a severe effect of most mutations in this exon that would be incompatible with life.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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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“…Since that observation, several FGFR1 mutations, all of which occurred in the FGFR1IIIc isoform and spanned all of the functional domains of the receptor, have been identified in KS-affected individuals and in patients with nICH. 26,27 Similar to KAL1 defects, other nonreproductive and non-olfactory disorders, such as cleft palate or lip, dental agenesis and bimanual synkinesis, are associated with KS due to FGFR1 defects. 15 An important phenotypic variability has been reported in mutated FGFR1 in unrelated probands and mixed pedigrees.…”

Section: Fgfr1 and Fgf8mentioning

confidence: 99%

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Bonomi¹,

Libri²,

Guizzardi³

et al. 2011

Asian J Androl

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Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network. Asian Journal of Andrology (2012) 14, 49-56; doi:10.1038/aja.2011.68; published online 5 December 201

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“…7,11 -13,65,73 Lastly, bimanual synkinesis is highly prevalent in KAL1 (maybe 475% of the cases), 17,22 but seems to be much less common in KAL2. 7,12 10 which could be related to the known function of prokineticin-2 signalling in behavioural circadian rhythms, including sleep -wake and ingestive behaviour. 74 The prevalence of sleeping and eating disorders in KS patients, however, remains to be determined.…”

Section: Genotype -Phenotype Correlationmentioning

confidence: 99%

Kallmann syndrome

2008

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The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

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Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia

Cited by 88 publications

References 34 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

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Kallmann syndrome

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