Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism.
OBJECTIVE
To determine the frequency of rare nucleotide variants in GNRHR and GPR54 in a large cohort of probands (n = 166) with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), characterized by mode of inheritance, testicular volume, and presence or absence of endogenous LH pulsations.


METHODS
Whenever possible, probands answered detailed questionnaires, underwent full physical exams, and underwent q 10-min frequent blood sampling for LH. Exons segments for GNRHR and GPR54 were screened for mutations. Nucleotide changes were identified as rare variants if they occurred at less than 1% frequency in an ethnically matched control population.


RESULTS
Sixty-two percent of male probands were classified as sporadic, meaning that no other family members had delayed puberty or nIHH. In contrast, 61% of female probands were from familial pedigrees, with either autosomal dominant or autosomal recessive inheritance. Patients displayed a broad spectrum of disease severity based on testicular size and endogenous LH pulsations. Twenty-four rare variants were identified in GNRHR (within 15 probands) and seven rare variants in GPR54 (within five probands).


CONCLUSIONS
Rare variants in GNRHR are more common than GPR54 in a nIHH population.
Cerrato
Felecia
F
Reproductive Endocrine Unit, Massachusetts General Hospital BHX 504, Fruit Street, Boston, Massachusetts 02114, USA.
Shagoury
Jenna
J
Kralickova
Milena
M
Dwyer
Andrew
A
Falardeau
John
J
Ozata
Metin
M
Van Vliet
Guy
G
Bouloux
Pierre
P
Hall
Janet E
JE
Hayes
Frances J
FJ
Pitteloud
Nelly
N
Martin
Kathryn A
KA
Welt
Corrine
C
Seminara
Stephanie B
SB
D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics*
C484844:GNRHR protein, human; C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH