Follicle-stimulating-hormone receptor and twinning 3
Sir—Ayman Al-Hendy and colleagues report on the association between mutations of the follicle-stimulatinghormone receptor (FSHR) (Sept 9, p 914)1 and repeated twinning. They describe a woman, bearing two mutations in the receptor, one change at position 307 (alanine to threonine) and the other with a change at position 680 (asparagine to serine), who delivered in each of the two pregnancies, one set of dizygotic twins. Such sequence changes, Al-Hendy and colleagues conclude, do not reflect common polymorphisms, since they were not found in 14 additional unrelated women, and should be taken as causative for the observed phenotype (repeated twinning). Although the hypothesis is interesting and the pedigree of the woman clearly suggests that genetic factors are involved, we have our doubts that the identified mutations are causative for this phenotype. The FSHR exists in two allelic variants displaying either alanine or threonine at position 307 and asparagine or serine at position 680. These allelic variants are equally present and distributed according to Mendelian laws in white people.2,3 Therefore, the Asn680Ser variant is not rare and we are surprised that Al-Hendy and colleagues did not detect it in their control group. Functional studies in vitro of the two receptor variants Thr307-Asn680 and Ala307-Ser680 have shown no significant differences for hormone binding and cAMP production in COS7 cells.4 The type of the FSHR variant does, however, determine the ovarian response to FSH stimulation in women undergoing in-vitro fertilisation, with the 680Ser variant displaying the lowest sensitivity to FSH.5 Al-Hendy and colleagues seem to have ignored evidence of such FSHR variants, which should not be thought of as mutations, but rather represent common polymorphisms. Therefore the conclusion that these genetic changes are causative for the observed twinning is wrong and scientifically misleading. To avoid any confusion in the scientific community based on this report, it should be withdrawn. *Jörg Gromoll, Manuela Simoni Institute of Reproductive Medicine, Domagkstrasse 11, D-48129 Münster, Germany (e-mail: [email protected]
Al-Hendy A, Moshynska O, Saxena A, Feyles V. Association between mutations of the follicle-stimulating-hormone receptor and repeated twinning. Lancet 2000; 356: 914. Simoni M, Gromoll J, Nieschlag E. The follicle stimulating hormone receptor:
biochemistry, molecular biology, physiology and pathophysiology. Endocr Rev 1997; 18: 739–73. Liu JY, Gromoll J, Cedars MI, LaBarbera AR. Identification of allelic variants in the follicle-stimulating hormone receptor genes of females with or without hypergonadotropic amenorrhea. Fertil Steril 1998; 70: 326–31. Simoni M, Gromoll J, Höppner W, et al. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms with different hormone affinity. J Clin Endocrinol Metab 1999; 84: 751–55. Perez M, Gromoll J, Sonntag B, Behre HM, Nieschlag E, Simoni M. Ovarian response to FSH stimulation depends on the FSH receptor genotpye. J Clin Endocrinol Metab 2000; 85: 3365–69.
Sir—Ayman Al-Hendy and colleagues1 report two linked mutations (Thr307Ala and Asn680Ser) in exon 10 of the FSHR gene in a woman who had had a strong family history of twinning and had given birth to two sets of dizygotic twins without fertility treatment. The two mutations were in linkage disequilibrium and always segregated together. The woman was homozygous (+/+) for the two mutations, but none of the other women in her family nor another 14 female controls showed homozygosity at this locus. They suggest that expression of the Ala307 and Ser680 mutations increases the sensitivity of the receptor to FSH, and homozygosity for these two mutations at the FSHR locus in women is associated with repeated spontaneous twinning. These two closely linked mutations were first described by M Simoni and colleagues.2 They are highly prevalent in women with premature ovarian failure and fertile controls with similar frequencies. Homozygosity of these two mutations was seen in the two groups of women studied.3 Ala307 and Ser680 allele was homozygous in 20% of the infertile men and 17·4% of the fertile controls.2 Moreover, the mutant FSHR showed functional characteristics similar to the normal FSHR.2 Truncation of the C-terminal tail, which eliminated the serine and threonine residues at the potential phosphorylation sites of the FSHR, did not impair or induce receptor phosphorylation and uncoupling.4 These results contradict the suggestion that addition of the Ser680 residue could contribute to a potential phosphorylation site involved in the receptor function. We have screened 124 women with polycystic ovarian disease and 236 fertile women for these two mutations, we found that ten (8·1%) of those with polycystic ovaries and 12 (5·1%) of the controls were homozygous for the Ala307 and Ser680 allele (p=0·258); no
homozygous carrier had a history of twinning. The frequency of Ala307 and Ser680 allele was 31·0% and 28·6% in patients with polycystic ovaries and controls, respectively. These two nucleotide transitions in exon 10 of FSHR gene are polymorphisms, which probably have little effect on the function of the FSHreceptor and result in twinning the homozygous carriers. The cause of twinning is thus probably due to factors other than these two FSH-receptor gene polymorphisms. *Wu Xiang Liao, *Ashim C Roy, Soon Chye Ng Department of Obstetrics and Gynaecology, National University of Singapore, National University Hospital, 119074, Singapore (e-mail: [email protected]
Al-Hendy A, Moshynska O, Saxena A, Feyles V. Association between mutations of the follicle-stimulating-hormone receptor and repeated twinning. Lancet 2000; 356: 914. Simoni M, Gromoll J, Höppner W, et al. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab 1999; 84: 751–55. da Fonte Kohek MB, Batista MC, Russell AJ, et al. No evidence of the inactivating mutation (C566T) in the folliclestimulating hormone receptor gene in Brazilian women with premature ovarian failure. Fertil Steril 1998; 70: 565–67. Hipkin RW, Liu X, Ascoli M. Truncation of the C-terminal tail of the follitropin receptor does not impair the agonist- or phorbol esterinduced receptor phosphorylation and uncoupling. J Biol Chem 1995; 270: 26683–89. Tong Y, Liao WX, Roy AC, Ng SC. Absence of mutations in the coding regions of folliclestimulating hormone receptor gene in Singapore Chinese women with premature ovarian failure and polycystic ovary syndrome. Horm Metab Res (in press).
Sir—Ayman Al-Hendy and colleagues1 suggest that homozygosity for two linked mutations (G/G homozygosity) at the FSHR gene in women produces a presumably more sensitive FSHR and is associated with repeated spontaneous twinning. They based their conclusion on one index case, homozygous for the G variant, and on the fact that no other female member of her family nor any of the other 14 female controls (data not shown) had homozygosity at this locus, which suggests that these mutations are not a common polymorphism of the FSHR locus in women in this population. As part of a project of the East Flanders Prospective Twin Survey2 we have collected data on Flemish pedigrees with many spontaneous dizygotic twins. Two families showed repeated spontaneous dizygotic twinning (figure). The pregnancies were conceived without the
THE LANCET • Vol 357 • January 20, 2001
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