First genetic characterization of Xeroderma pigmentosum in Libya: High frequency of XP-C founder mutation.

BACKGROUND: Xeroderma pigmentosum is an autosomal recessive disease characterized by a high sensitivity to UV radiations. The disease is clinically and genetically heterogeneous, thus making accurate early clinical diagnosis difficult. Although the disease is considered rare worldwide, previous studies have shown that it is more frequent in Maghreb countries. So far, no genetic study has been published on Libyan patients, except three reports limited to clinical descriptions. METHODS: Our study, which represents the first genetic characterization of XP in Libya, was conducted on 14 unrelated families including 23 Libyan XP patients with a consanguinity rate of 93%. Blood samples were collected from 201 individuals including patients and their relatives. Patients were screened for founder mutations already described in Tunisia. RESULTS: The two founder Maghreb XP mutations, XPA p.Arg228* associated with the neurological form and XPC p.Val548Alafs*25 in patients with only cutaneous manifestations, were homozygously identified. The latter was predominant (19 of 23 patients). In addition, another XPC homozygous mutation (p.Arg220*) has been identified in only one patient. For the remaining patient, the absence of founder XPA, XPC, XPD, and XPG mutations suggests mutational heterogeneity of XP in Libya. CONCLUSION: Identification of common mutations with other Maghreb populations is in favor of a common ancestor in North-African populations.

Uterine Wnt/beta-catenin signaling is required for implantation.

Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt/beta-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt/beta-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt/beta-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt/beta-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.

Expression and estradiol regulation of Wnt genes in the mouse blastocyst identify a candidate pathway for embryo-maternal signaling at implantation.

Implantation of mammalian embryos depends on differentiation of the blastocyst to a competent state and of the uterine endometrium to a receptive state. Communication between the blastocyst and uterus ensures that these changes are temporally coordinated. Although considerable evidence indicates that the blastocyst induces expression of numerous genes in uterine tissue, potential signaling mechanisms have yet to be identified. Moreover, whereas a surge of maternal estradiol occurring on Day 4 of pregnancy in the mouse is critically required for many of the peri-implantation uterine changes, whether this surge also affects blastocyst gene expression has not been established. We show here that mouse morulae express genes encoding several members of the Wnt family of signaling molecules. Additional Wnt genes are newly expressed following development to blastocyst. Unexpectedly, Wnt5a and Wnt11 are expressed in embryos that undergo the morula-to-blastocyst transition in vivo, but only weakly or not at all in embryos that do so in vitro. Upregulation of Wnt11 is temporally coordinated with the surge of maternal estradiol on Day 4. Wnt11 fails to be upregulated in blastocysts obtained from mice ovariectomized early on Day 4 or from mice treated with the estradiol antagonist, ICI 182,780. Administration of estradiol-17beta or its metabolite, 4-OH-estradiol, to ovariectomized mice restores Wnt11 expression. Moreover, Wnt11 expression is not upregulated when blastocysts are trapped in the oviduct following ligation of the utero-tubal junction, nor when estradiol-17beta or 4-OH-estradiol are administered to blastocysts in vitro. These results establish a comprehensive profile of Wnt gene expression during late preimplantation development, demonstrate that estradiol regulates gene expression in the blastocyst via uterine factors, and identify Wnts as potential mediators of embryo-uterine communication during implantation.