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Endocrinology Vol. 140, No. 8 3496-3506
Copyright © 1999 by The Endocrine Society

ARTICLES

A Naturally Occurring Genetic Variant in the Human Chorionic Gonadotropin-ß Gene 5 Is Assembly Inefficient1

Amanda K. Miller-Lindholm2, Elliott Bedows, Cynthia F. Bartels, Jacques Ramey, Victoria Maclin and Raymond W. Ruddon3

Eppley Institute for Research in Cancer and Allied Diseases (A.K.M.-L., E.B., C.F.B., R.W.R.), the Departments of Biochemistry and Molecular Biology (A.K.M.-L., R.W.R.), Pharmacology (E.B., R.W.R.), and Obstetrics and Gynecology (E.B., J.R.. V.M.), University of Nebraska Medical Center, Omaha, Nebraska 68198

Address all correspondence and requests for reprints to: Dr. Elliott Bedows, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805. E-mail: ebedows{at}unmc.edu

The hCGß gene family is composed of six homologous genes linked in tandem repeat on chromosome 19; the order of the genes is 7, 8, 5, 1, 2, and 3. Previous studies have shown that hCGß gene 5 is highly expressed during the first trimester of pregnancy. The purpose of our study was to identify naturally occurring polymorphisms in hCGß gene 5 and determine whether these alterations affected hCG function. The data presented here show that hCGß gene 5 was highly conserved in the 334 asymptomatic individuals and 41 infertile patients examined for polymorphisms using PCR followed by single stranded conformational polymorphism analysis. Most of the polymorphisms detected were either silent or located in intron regions. However, one genetic variant identified in ß gene 5 exon 3 was a G to A transition that changed the naturally occurring valine residue to methionine in codon 79 (V79M) in 4.2% of the random population studied. The V79M polymorphism was always linked to a silent C to T transition in codon 82 (tyrosine). To determine whether ßV79M hCG had biological properties that differed from those of wild-type hCG, a ß-subunit containing the V79M substitution was created by site-directed mutagenesis and was coexpressed with the glycoprotein hormone {alpha}-subunit in Chinese hamster ovary cells and 293T cells. When we examined ßV79M hCG biosynthesis, we detected atypical ßV79M hCG folding intermediates, including a ßV79M conformational variant that resulted in a ß-subunit with impaired ability to assemble with the {alpha}-subunit. The inefficient assembly of ßV79M hCG appeared to be independent of ß-subunit glycosylation or of the cell type studied, but, rather, was due to the inability of the ßV79M subunit to fold correctly. The majority of the V79M ß-subunit synthesized was secreted as unassembled free ß. Although the amount of {alpha}ß hCG heterodimer formed and secreted by ßV79M-producing cells was less than that by wild-type ß-producing cells, the hCG that was secreted as {alpha}ß V79M heterodimer exhibited biological activity indistinguishable from that of wild-type hCG.




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