Mutations and polymorphisms in gonadotropin genes

Huhtaniemi, Ilpo; Jiang, Min; Nilsson, Christel; Pettersson, Kim

doi:10.1016/s0303-7207(99)00015-5

Cited by 63 publications

(25 citation statements)

References 37 publications

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“…Some of mutations, Val and Ile, resulted in strikingly high basal cAMP levels, despite lower receptor concentrations on the surface. This is unusual because all activating mutations uncovered to date are found in the endodomain (11,46). A simple explanation is that the region may be involved in signal generation in the endodomain.…”

Section: Constitutive Activation Of Camp Induction By Substitution Fomentioning

confidence: 99%

The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation

Zeng¹,

Phang²,

Song³

et al. 2001

Journal of Biological Chemistry

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Luteinizing hormone receptor, a G protein-coupled receptor, consists of two halves, the N-terminal extracellular hormone binding domain (exodomain) and the Cterminal membrane-associated, signal-generating domain (endodomain). The exodomain has seven to nine Leu-rich repeats, which are generally thought to form a 1/3 donut-like structure and interact with human choriogonadotropin (hCG). The resulting hCG-exodomain complex adjusts the structure and its association with the endodomain, which results in signal generation in the endodomain. It is unclear whether the rigid 1/3 donut structure could provide the agility and versatility of this dynamic action. In addition, there is no clue as to where the endodomain contact point (the signal modulator) in the exodomain is. To address these issues, the exodomain was examined by Ala scan and multiple substitutions, while receptor peptides were used for photoaffinity labeling and affinity cross-linking. Our results show that the C-flanking sequence (hinge region), Thr 250 -Gln 268 , of the Leu-rich repeats (LRRs) specifically interacts with hCG, preferentially hCG␣. This interaction is inhibited by exoloop 2 of the endodomain but not by exoloops 1 and 3, suggesting an intimate relationship between Thr 250 -Gln 268 , exoloop 2, and hCG. Taken together, our observations in this article suggest a new paradigm that the LRRs contact the front of hCG, while both flanking regions of the LRRs interact with the sides of hCG. This would trap hCG in the 1/3 donut structure of the LRRs and enhance the binding affinity. In addition, mutations of conserved Ser 255 in the sequence can constitutively activate the receptor. This provides a clue for the signal modulator in the exodomain. In contrast, a phenyl or phenolic group is necessary at conserved Tyr 253 for targeting the receptor to the surface.

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Section: Constitutive Activation Of Camp Induction By Substitution Fomentioning

confidence: 99%

The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation

Zeng¹,

Phang²,

Song³

et al. 2001

Journal of Biological Chemistry

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“…17 The frequency of the variant LHb, which consists of two point missense mutations leading to two amino-acid substitutions (Trp 8 -Arg 8 and Ile 15 -Thr 15 ), 5,6 differs widely between ethnic groups, from 0 to 52%. 7 Based on the structure of hCGb, variant LHb and wild-type LHb, it is possible that the variant LHb appeared through gene conversion within the LHb/hCGb gene cluster, which may be predisposed to genetic recombination. 1 It is also possible that variant LH represents an ancestral LH form, which is being replaced by wild-type LH.…”

Section: Discussionmentioning

confidence: 99%

“…1 This process seems to be at different stages in different populations, as judged from the vast ethnic differences in frequency of allele at the two LHb subunit. 7 The reason for this remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…4 In general, the variant forms of LH do not correlate with gynaecological diseases, including infertility. However, it is of particular interest to note that the frequency of the variant LHb containing two missense point mutations differs widely between ethnic groups, varying from 0 to 52%, 7 and the homozygotes for variant LH in the Finnish population are apparently healthy with no reported infertility or subfertility, while in the Japanese population variant LH is related to infertility and various menstrual disorders. 6,8 -10 We report here extremely high frequencies of novel allele in Japanese, and the relationship between two missense mutations and five silent mutations in the LHb gene, and ovulatory disorders in Japanese women.…”

Section: Introductionmentioning

confidence: 99%

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Influence of missense mutation and silent mutation of LHβ-subunit gene in Japanese patients with ovulatory disorders

et al. 2003

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The frequency of variant LHb containing two point mutations (T 986 -C and T 1008 -C) and its relationship to reproductive disorders differ widely between ethnic groups. In a Japanese population, variant luteinizing hormone (LH) correlates with ovulatory disorders. Here we examined the relationship between two missense mutations and five silent mutations (C 894 -T, G 1018 -C, C 1036 -A, C 1098 -T and C 1423 -T) in the LHb gene, and ovulatory disorders. We studied 43 patients with ovulatory disorders, 79 patients with normal ovulatory cycles, and 23 healthy men who agreed to join our DNA analysis. PCR-amplified LHb-subunit gene sequences were compared with a base sequence of wild-type LH reported after direct sequencing. The highest frequency (0.945) of novel allele was observed at the position of the C 1036 -A transition. No homozygotes for wild-type LHb (C 1036 ) were identified. The frequency of novel allele in patients with polycystic ovary syndrome, endometriosis, premature ovarian failure and luteal insufficiency was significantly different from that of healthy women. The frequencies of novel alleles (C 894 -T, C 1098 -T and C 1423 -T) in patients with ovulatory disorders were significantly higher than those with normal ovulatory cycles. The mean incidence of point mutation in patients with ovulatory disorders was higher than in those with normal ovulatory cycles. Among patients with variant LH, five silent mutations were identified in 87.5% of patients with ovulatory disorders, whereas only a few silent mutations were identified in patients with normal ovulatory cycles. In a Japanese population, five silent mutations of variant LH could have influenced two missense mutations and/or other unknown missense mutations, causing ovulatory disorders.

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“…(Alliende, 2002;Birken et al, 1999;Huhtaniemi et al, 1999) (Ramanujam et al, 1999;Tulppala et al, 1998) (Matt et al, 1998;Ropelato et al, 1999;Takahashi et al, 2001;Van Dam et al, 2002;Veldhuis and Pincus, 1998). Virtually all studies of these glycoprotein hormones have been conducted using blood sampling which allows detailed hormone monitoring only for research subjects (Clark et al, 1997;Veldhuis et al, 1993;Veldhuis and Pincus, 1998) (Clark et al, 1997;Veldhuis, 1997).…”

Section: Introductionmentioning

confidence: 99%

Patterns of LHβcf among women in health and disease

Birken

McChesney

Yershova

et al. 2007

Molecular and Cellular Endocrinology

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Urine based gonadotropin assays provide a practical means of analyzing hormone secretion patterns. While research protocols have revealed pulsatile patterns of gonadotropins such as LH in the blood, these assays are of limited clinical use since daily venipuncture sampling is not feasible outside of a research environment. However, collection of several urine samples provides a method to achieve the same visualization of gonadotropin patterns in patients using a convenient and generally applicable technique based on analysis of the highly stable hLHβcf for monitoring LH and hCGβcf for monitoring pituitary hCG. We demonstrated that two different sampling techniques for analyzing these gonadotropin metabolites yielded the same information on their excretory patterns, either sampling of spot urines or collecting first morning void urines for several days. Next, we studied the core excretory patterns in several populations: menstruating and postmenopausal women from the general population, and two populations of women from a fertility center, one of which had polycystic ovaries (PCO). The PCO population was also subdivided into those with and without insulin resistance (IR). It was found that our hLHβcf assay did not measure the form of the LH core (vhLHβcf) produced in subjects who were homozygous for a variant form of LH (v-LH). None of our patients tested were homozygous for the variant form of LH. It was also found that in most non-PCO (NPCO) patients, the hLHβcf peak lasted for 7-9 days while among the PCO patients this peak frequently lasted for less than 7 days and an erratic pattern tended to appear. The overall differences in patterns between the PCO and NPCO patients were confirmed by spectral statistical methods. The prevalence of certain characteristic hLHβcf patterns may be higher among women with PCO with a more severe clinical presentation. Use of urinary analysis of gonadotropin metabolites, especially hLHβcf, may supplement subjective ultrasound studies with more sensitive biochemical measurements.

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Mutations and polymorphisms in gonadotropin genes

Cited by 63 publications

References 37 publications

The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation

The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation

Influence of missense mutation and silent mutation of LHβ-subunit gene in Japanese patients with ovulatory disorders

Patterns of LHβcf among women in health and disease

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