Genetic evidence of 'genuine' empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature.
Empty follicle syndrome (EFS) is a reproductive disorder in which no oocytes are retrieved during IVF. The existence of genuine EFS (GEFS) is still controversial, and to date, only one missense mutation of Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) has been reported to be associated with this disease. Here, we describe a GEFS patient in a non-consanguineous family from China. A 27-year-old woman presented with a 5-year history of primary infertility and LH resistance-like ovaries of unequal sizes, but with normal levels of circulating LH. In spite of a satisfactory ovarian reserve and response, no oocytes were retrieved after two cycles of IVF. Her condition did not appear to be failure of the hCG injection. It is more likely to be a genetic cause. A novel homozygous mutation in LHCGR gene, c.1345G>A (p.Ala449Thr), was detected in this patient. Each of her parents is heterozygous for this change, and the change was absent from 407 control subjects. Alanine at this amino acid position was highly conserved and replacement of threonine was predicted to disrupt the third transmembrane helix of the rhodopsin-like G protein-coupled receptor domain. Protein localization studies revealed that a portion of the mutant LHCGR protein molecules was retained intracellularly. Signalling studies demonstrated that this mutation had differing effects on the response of LHCGR to hCG or LH at different concentrations. Specifically, at a concentration <1 IU/ml, the mutant was activated by hCG stimulation but partially resistant to LH stimulation; at a higher concentration (>1 IU/ml), the mutant was activated by both hCG and LH. These data suggest that screening for mutations in the LHCGR gene may assist in the diagnosis of patients with GEFS. The literature describing the relationship between phenotype and genotypes in females is reviewed, and possible aetiologies and treatment options for this disease are proposed based on our and other studies.
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Ping
P
Yuan
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
Zuyong
Z
He
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Lingyan
L
Zheng
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Wenjun
W
Wang
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Yu
Y
Li
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Haijing
H
Zhao
Department of Molecular and Human Genetics, Baylor College of Medicine, one Baylor Plaza, Houston, TX, US.|AmCare Genomics Laboratory, International BioIsland, Guangzhou, Guangdong, China.
Victor Wei
VW
Zhang
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Qingxue
Q
Zhang
Department of Obstetrics and Gynecology, IVF Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong , China.
Dongzi
D
Yang
D019943:Amino Acid Substitution; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000473:pathology; D054315:Oocyte Retrieval; D009865:Oocytes / Q000254:growth & development; D010049:Ovarian Diseases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
D011974:Receptors, LH
LHCGR; activating; empty follicle syndrome; mutation; partially inactivating