Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit.

Molecular Human Reproduction
Liina NagirnajaMaris Laan

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 st...Continue Reading

References

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Citations

Nov 29, 2013·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·Janet Choi, Johan Smitz
Sep 29, 2018·Minerva ginecologica·Kamila SzymańskaAdolfo Rivero-Müller
Jul 9, 2016·Molecular Endocrinology·Gunnar KleinauAnnette Grüters-Kieslich
May 16, 2014·Human Mutation·Liina NagirnajaMaris Laan
Nov 11, 2019·International Journal of Molecular Sciences·Laura KalveramHeike Biebermann

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Methods Mentioned

BETA
PCR
genotyping
transfection
co-immunoprecipitation
protein assay
Immunoprecipitation
electrophoresis
X-ray
transfections
ELISA

Software Mentioned

DSSP
GraphPad Prism
WebLogo
ClustalW2
PrimerX
Voroprot
GROMACS
BLAST

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