Leukaemia inhibitory factor gene mutations in infertile women.

The glycoprotein leukaemia inhibitory factor (LIF) is produced by the endometrium and is involved in the control of implantation. In women with unexplained infertility reduced uterine concentrations of LIF have been reported. Studies with mice lacking a functional LIF gene have shown that the LIF protein is essential for implantation of the embryo. We have developed a method for screening of gene mutations in the coding region and critical regulatory regions of the LIF gene. Thus we could screen nulligravid infertile women (n = 74), fertile controls (n = 75) and as a second unrelated control group, neurological patients (n = 131) for LIF gene mutations. In infertile women, three heterozygous point mutations have been identified: one in close proximity to the start codon of exon 1 and two mutations in exon 3. These correspond to regions of the LIF protein which are thought to be highly important for interaction with the LIF receptor and thus lead to reduced biological activity of the LIF protein. Only one point mutation/polymorphism in the non-coding region between exon 2 and 3 was found in the control groups. Our results suggest that heterozygosity for a LIF gene mutation could give rise to decreased availability or biological activity of LIF in the uterus and cause implantation failure. Thus the mutations identified in our study could be responsible for infertility in a subgroup of nulligravid women.