Genomics and genetics of gonadotropin beta-subunit genes: Unique FSHB and duplicated LHB/CGB loci

Nagirnaja, Liina; Rull, Kristiina; Uusküla, Liis; Hallast, Pille; Grigorova, Marina; Laan, Maris

doi:10.1016/j.mce.2010.04.024

Cited by 69 publications

(54 citation statements)

References 119 publications

(88 reference statements)

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“…Coincident with this event, the single pituitary gonadotropic hormone that exists in primitive vertebrates has given rise to two gonadotropins, FSH and luteinizing hormone (LH), which coordinate gametogenesis and steroidogenesis (3)(4)(5)(6)(7). FSH and LH are heterodimeric glycoproteins that contain a common α-subunit and a hormonespecific β-subunit (3).…”

mentioning

confidence: 99%

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

Wang¹,

Larson²,

Jablonka‐Shariff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.protein sorting | regulated secretion | dense core granules | folliculogenesis

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mentioning

confidence: 99%

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

Wang¹,

Larson²,

Jablonka‐Shariff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The V‐LHβ polymorphism was suggested to have originated through an ancient gene conversion event, where one of the hCGβ encoding CGB genes has acted as a conversion donor and the LHB gene as an acceptor of the respective genomic fragment (Hallast et al ., 2005). The concerted substitutions in V‐LH exon 2 leading to Trp8Arg/Ile15Thr correspond to the nucleotide sequence in the respective positions of all six CGB genes (Nagirnaja et al ., 2010). Because of the Trp8Arg/Ile15Thr substitutions in the encoded LHβ subunit it resembles the more stable hCGβ and subsequently, the V‐LH has a prolonged half‐life compared to WT‐LH.…”

Section: Discussionmentioning

confidence: 99%

“…Although the V‐LH was reported to possess an increased in vitro bioactivity (Manna et al ., 2002), most clinical observations suggest that V‐LH is functionally less potent than WT‐LH (Nagirnaja et al ., 2010). Case–control association studies in male patients have suggested V‐LH as a risk factor for cryptorchidism (Kaleva et al ., 2005) and testicular cancer (Elkins et al ., 2003).…”

Section: Introductionmentioning

confidence: 99%

“…One of the reasons might be that the majority of association studies with V‐LH have been carried out on relatively small patient groups and for limited sets of clinical parameters (Nagirnaja et al ., 2010). In addition, most of the studies have determined V‐LH using a technically demanding immunoassay‐based approach, which measures the two alternative isoforms of LH.…”

Section: Introductionmentioning

confidence: 99%

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‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

et al. 2015

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SummaryLuteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V‐LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β‐subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V‐LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V‐LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V‐LH was detected by genotyping of the underlying DNA polymorphisms using PCR‐RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta‐analysis. No significant difference was detected between young men and infertility patients for the V‐LH allele frequency (11.0 vs. 9.3%, respectively). V‐LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta‐analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V‐LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB ‐211G/T, FSHR Asn680Ser, FSHR ‐29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V‐LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V‐LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

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“…CGB5 is one of the most actively transcribed genes among the six CGB genes [11]. CGB5 is regarded as the major contributor of hCG function during pregnancy [6,12].…”

Section: Introductionmentioning

confidence: 99%

Association of rs7260002 of chorionic gonadotrophin β5 with idiopathic recurrent spontaneous abortion in Chinese population

Sun

2014

J Assist Reprod Genet

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Purpose Low levels of serum hCG during the first trimester is regarded as a predictor of miscarriage. This study was designed to examine whether variance in chorionic gonadotrophin β5 (Cgb5) gene confers risk to recurrent spontaneous abortions (RSA) in Chinese women. Methods We recruited a total of 454 RSA subjects and 460 controls from our medical center between the years 2010 to 2013. rs7260002, which resides in the promoter region of Cgb5, was genotyped through direct sequencing. Results The carriers with the minor allele of rs7260002 had reduced risk of RSA (P=0.018; P adjusted=0.032; OR: 0.76; 95 % CI: 0.61-0.96). Genotype frequency was further analyzed under additive, recessive, and dominant models. Significant differences between the RSA subjects and controls were detected under additive and recessive models (P additive= 0.040; P recessive=0.010). Conclusions The current study identified a protective allele of the Cgb5 gene against RSA. Functional studies are required to elucidate the effect of the identified SNP on CGB expression and HCG hormone activity.

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Genomics and genetics of gonadotropin beta-subunit genes: Unique FSHB and duplicated LHB/CGB loci

Cited by 69 publications

References 119 publications

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

Association of rs7260002 of chorionic gonadotrophin β5 with idiopathic recurrent spontaneous abortion in Chinese population

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