Article

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

Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.
Molecular and Cellular Endocrinology (Impact Factor: 4.24). 11/2010; 329(1-2):4-16. DOI: 10.1016/j.mce.2010.04.024
Source: PubMed

ABSTRACT The follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (HCG) play a critical role in human reproduction. Despite the common evolutionary ancestry and functional relatedness of the gonadotropin hormone beta (GtHB) genes, the single-copy FSHB (at 11p13) and the multi-copy LHB/CGB genes (at 19q13.32) exhibit locus-specific differences regarding their genomic context, evolution, genetic variation and expressional profile. FSHB represents a conservative vertebrate gene with a unique function and it is located in a structurally stable gene-poor region. In contrast, the primate-specific LHB/CGB gene cluster is located in a gene-rich genomic context and demonstrates an example of evolutionary young and unstable genomic region. The gene cluster is shaped by a constant balance between selection that acts on specific functions of the loci and frequent gene conversion events among duplicons. As the transcription of the GtHB genes is rate-limiting in the assembly of respective hormones, the genomic and genetic context of the FSHB and the LHB/CGB genes largely affects the profile of the hormone production.

Download full-text

Full-text

Available from: Kristiina Rull, Jul 28, 2015
1 Follower
 · 
119 Views
  • Source
    • "The unique functions and receptor-binding capacity of each of these hormones stem from differences among the b subunits (Table 1). Transcription of the b-subunit is the rate-limiting step in LH and CG production (Nagirnaja et al., 2010). The genes for the LH and hCG b subunits are located within a cluster of seven similar sequences on human chromosome 19q13.32 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are widely recognized for their roles in ovulation and the support of early pregnancy. Aside from the timing of expression, however, the differences between LH and hCG have largely been overlooked in the clinical realm because of their similar molecular structures and shared receptor. With technologic advancements, including the development of highly purified and recombinant gonadotropins, researchers now appreciate that these hormones are not as interchangeable as once believed. Although they bind to a common receptor, emerging evidence suggests that LH and hCG have disparate effects on downstream signaling cascades. Increased understanding of the inherent differences between LH and hCG will foster more effective diagnostic and prognostic assays for use in a variety of clinical contexts and support the individualization of treatment strategies for conditions such as infertility.
    Molecular and Cellular Endocrinology 12/2013; 383(1-2). DOI:10.1016/j.mce.2013.12.009 · 4.24 Impact Factor
  • Source
    • "The structural and functional properties of the subunits are determined by six cystine bonds and six oligosaccharide chains (two N-linked, four O-linked) in hCGb and five cystine bonds and two N-linked carbohydrates in the a-subunit (Morgan et al., 1975; Lapthorn et al., 1994). The chorionic gonadotrophin beta (CGB) genes encoding the hCG b-subunit (145 aa) have evolved in the primate lineage by serial duplications of the ancestral LH b-subunit coding gene (LHB) (Maston and Ruvolo, 2002; Hallast et al., 2008; Nagirnaja et al., 2010). In humans, the common gene cluster for LHB and six CGB genes is located at 19q13.32 (Policastro et al., 1986). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterodimeric hCG is one of the key hormones determining early pregnancy success. We have previously identified rare missense mutations in hCGβ genes with potential pathophysiological importance. The present study assessed the impact of these mutations on the structure and function of hCG by applying a combination of in silico (sequence and structure analysis, molecular dynamics) and in vitro (co-immunoprecipitation, immuno- and bioassays) approaches. The carrier status of each mutation was determined for 1086 North-Europeans [655 patients with recurrent miscarriage (RM)/431 healthy controls from Estonia, Finland and Denmark] using PCR-restriction fragment length polymorphism. The mutation CGB5 p.Val56Leu (rs72556325) was identified in a single heterozygous RM patient and caused a structural hindrance in the formation of the hCGα/β dimer. Although the amount of the mutant hCGβ assembled into secreted intact hCG was only 10% compared with the wild-type, a stronger signaling response was triggered upon binding to its receptor, thus compensating the effect of poor dimerization. The mutation CGB8 p.Pro73Arg (rs72556345) was found in five heterozygotes (three RM cases and two control individuals) and was inherited by two of seven studied live born children. The mutation caused ~50% of secreted β-subunits to acquire an alternative conformation, but did not affect its biological activity. For the CGB8 p.Arg8Trp (rs72556341) substitution, the applied in vitro methods revealed no alterations in the assembly of intact hCG as also supported by an in silico analysis. In summary, the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCGβ genes CGB5 and CGB8.
    Molecular Human Reproduction 05/2012; 18(8):379-90. DOI:10.1093/molehr/gas018 · 3.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Corifollitropin alfa (also referred to originally as follicle-stimulating hormone [FSH]--carboxi terminal peptide and Org-36286) is a new artificial gonadotropin commercially available for women undergoing controlled ovarian follicle stimulation for IVF or intracytoplasmic sperm injection procedures. It is an artificial chimeric recombinant FSH analog, and its development has taken more than 20 years in order to show its functionality, safety and efficacy. Corifollitropin alfa has a similar functionality to natural FSH but with a longer half-life, among different pharmacokinetic parameters. This has allowed for the development of a new protocol with gonadotropin-releasing hormone antagonists, where the first seven daily injections of 150 IU recombinant have been substituted by a single initial 100 or 150 µµg Corifollitropin alfa dose with no safety or efficacy differences, measured by either the number of retrieved oocytes or pregnancy rates.
    Expert Review of Obstetrics &amp Gynecology 06/2011; 6(4):395-402. DOI:10.1586/eog.11.36
Show more