Submicroscopic deletion involving the &lt;i&gt;fibroblast growth factor receptor 1&lt;/i&gt; gene in a patient with combined pituitary hormone deficiency

Fukami, Maki; Iso, Manami; Sato, Naoko; Igarashi, Maki; Seo, Misuzu; Kazukawa, Itsuro; Kinoshita, Eiichi; Dateki, Sumito; Ogata, Tsutomu

doi:10.1507/endocrj.ej13-0023

Cited by 16 publications

(15 citation statements)

References 14 publications

(20 reference statements)

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“…The functional study performed by us ( Fig. 1 ) revealed no difference in transactivation in comparison with the WT, confirming the findings of the previous Japanese population study (23) . Taking into account the presence of the variant in Japanese controls and population databases, an unaffected first-degree relative carrying the variant, and the in vitro data, it is unlikely that this variant (p.Ser107Leu) alone is causing the phenotype.…”

Section: Discussionsupporting

confidence: 89%

“…This patient had GH, LH and FSH deficiencies associated with anosmia and spherocytosis (22) . Another submicroscopic deletion involving FGFR1 , identified during a study analysing 69 Japanese patients with CPHD, was detected in a female patient with CPHD associated with epilepsy, learning disability and Chiari type 1 malformation (23) . In addition to the submicroscopic deletion, in this study, two heterozygous missense variants (p.Val102Iso and p.Ser107Leu) were also found in two unrelated patients.…”

Section: Discussionmentioning

confidence: 91%

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FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies

Correa¹,

Trarbach²,

Tusset³

et al. 2015

Endocrine Connections

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The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2 + pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies

Correa¹,

Trarbach²,

Tusset³

et al. 2015

Endocrine Connections

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“…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%

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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“…She presented with a combined deficiency of GH, LH and FSH, central hypothyroidism and multiple neurological abnormalities. The phenotype of this patient suggests that FGFR1 abnormalities can be associated with various developmental defects of the anterior midline in the forebrain [58].…”

Section: Septo-optic Dysplasia and Other Eye Abnormalitiesmentioning

confidence: 82%

Congenital Hypopituitarism: Various Genes, Various Phenotypes

et al. 2019

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The ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

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Submicroscopic deletion involving the <i>fibroblast growth factor receptor 1</i> gene in a patient with combined pituitary hormone deficiency

Cited by 16 publications

References 14 publications

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies

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

Congenital Hypopituitarism: Various Genes, Various Phenotypes

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