When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).
Details
Serval ID
serval:BIB_91924C04E62C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).
Journal
Journal of Clinical Endocrinology and Metabolism
ISSN
1945-7197 (Electronic)
ISSN-L
0021-972X
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
97
Number
9
Pages
E1798-E1807
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural
Abstract
CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations.
OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR.
SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes.
RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes.
CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.
OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR.
SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes.
RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes.
CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.
Keywords
Adolescent, Adult, Amenorrhea/genetics, DNA/genetics, DNA Mutational Analysis, Ethnic Groups, Female, Genetic Load, Gonadotropin-Releasing Hormone/deficiency, Gonadotropin-Releasing Hormone/genetics, Humans, Hypogonadism/genetics, Hypothalamic Diseases/genetics, Male, Mutation/genetics, Phenotype, Puberty, Delayed/genetics, Receptors, LHRH/genetics, Receptors, LHRH/physiology, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
31/12/2012 13:25
Last modification date
20/08/2019 15:54