&lt;i&gt;FGFR1&lt;/i&gt; Mutations in Kallmann Syndrome

Villanueva, Carine; Roux, Nicolas de

doi:10.1159/000312693

Cited by 35 publications

(30 citation statements)

References 36 publications

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“…). The clinical manifestations of FGFR1 alterations are very heterogeneous since loss‐of‐function mutations in FGFR1 have been linked to Kallman syndrome [Dode et al., ; Albuisson et al., ; Villanueva and de Roux, ], hypogonadotropic hypogonadism with or without anosmia [Costa‐Barbosa et al., ; Vizeneux et al., ; Villanueva et al., ], and Hartsfield syndrome [Simonis et al., ; Hong et al., ]. Gain‐of‐function mutations in FGFR1 have also been identified in about 5% of Pfeiffer syndrome with or without craniosynostosis [Chokdeemboon et al., ].…”

Section: Discussionmentioning

confidence: 99%

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

et al. 2016

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Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

et al. 2016

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“…FGFR1 mutations account for approximately 10% of IHH patients. Patients with the same FGFR1 mutations can have severe hypogonadism or reversible phenotypes [50,51]. …”

Section: Etiopathogenymentioning

confidence: 99%

Pathology or Normal Variant: What Constitutes a Delay in Puberty?

Villanueva

Argente²

2014

Horm Res Paediatr

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Puberty is a complex maturation process that begins during fetal life and persists until the acquisition of reproduction function. The fundamental event that activates puberty occurs in the hypothalamus. A complex neuron network stimulates GnRH secretion, which stimulates pituitary gonadotropin secretion and then gonadal steroid secretion. Pubertal delay is defined as the presentation of clinical signs of puberty 2-2.5 SD later than in the normal population. Three major groups of etiopathogeneses are described: (1) hypogonadotropic hypogonadism, (2) hypergonadotropic hypogonadism, and (3) constitutional delay of puberty (CDP) - the most common cause of delayed puberty in boys. The differential diagnosis between CDP and isolated hypogonadotropic hypogonadism remains difficult. Mechanisms of pubertal timing are now better understood and genetic or epigenetic causes can explain some pubertal delays. However, there are still unexplained mechanisms. Treatment of delayed puberty is necessary to ensure full pubertal development for the adolescent and in case of hypogonadism, to restore fertility. Finally, precocious diagnosis of hypogonadism is primordial but can be difficult during childhood and in cases of partial hypogonadism. The study of genetic pubertal diseases or of different animal models could help to discover new diagnostic or therapeutic tools.

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“…8 Here, we detected a genetic mutation of the currently reported repertoire of involved genes in five of the seven pedigrees in this study. For individual genes, it has been reported that KAL1, FGFR1, and PROK2/PROKR2 mutations account for 10-14%, 30 10%, 31 and 9% 32 of all KS, respectively. The present study is a report of the largest cohort of Han Chinese ethnic patients (an ethnic group that comprises more than 90% of the population of mainland China) with inherited KS.…”

Section: Discussionmentioning

confidence: 99%

Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients

Zhang

Wang

et al. 2015

Exp Biol Med (Maywood)

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Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron-exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients' sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype-phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.

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<i>FGFR1</i> Mutations in Kallmann Syndrome

Cited by 35 publications

References 36 publications

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Pathology or Normal Variant: What Constitutes a Delay in Puberty?

Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients

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