Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

Details

Serval ID
serval:BIB_BA4B4A2F9266
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.
Journal
Neuroendocrinology
Author(s)
Barraud S., Delemer B., Poirsier-Violle C., Bouligand J., Mérol J.C., Grange F., Higel-Chaufour B., Decoudier B., Zalzali M., Dwyer A.A., Acierno J.S., Pitteloud N., Millar R.P., Young J.
ISSN
1423-0194 (Electronic)
ISSN-L
0028-3835
Publication state
Published
Issued date
2021
Peer-reviewed
Oui
Volume
111
Number
1-2
Pages
99-114
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs.
The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met.
This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
Keywords
Gonadotropin-releasing hormone, Gonadotropin-releasing hormone deficiency, Gorlin-Goltz syndrome, HedgeHog, Hypogonadotropic hypogonadism, Kallmann syndrome, Nevoid basal cell carcinoma syndrome
Pubmed
Web of science
Create date
09/10/2020 11:20
Last modification date
06/01/2021 6:25
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