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Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency

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Abstract
Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3-10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD.

Methods This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies.

Results Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations.

Conclusions This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.
Author(s)
최진호오아름이예나김구환유한욱
Issued Date
2021
Type
Article
Keyword
anosmiadelayed pubertyFGFR1hypogonadotropic hypogonadismKallmann syndrome
DOI
10.1055/a-1151-4800
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7597
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_crossref_primary_10_1055_a_1151_4800&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Functional%20Characteristics%20of%20Novel%20FGFR1%20Mutations%20in%20Patients%20with%20Isolated%20Gonadotropin-Releasing%20Hormone%20Deficiency&offset=0&pcAvailability=true
Publisher
EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY DIABETES
Location
독일
Language
영어
ISSN
0947-7349
Citation Volume
129
Citation Number
6
Citation Start Page
457
Citation End Page
463
Appears in Collections:
Medicine > Medicine
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