Rescue of placental phenotype in a mechanistic model of Beckwith-Wiedemann syndrome.

BACKGROUND: Several imprinted genes have been implicated in the process of placentation. The distal region of mouse chromosome 7 (Chr 7) contains at least ten imprinted genes, several of which are expressed from the maternal homologue in the placenta. The corresponding paternal alleles of these genes are silenced in cis by an incompletely understood mechanism involving the formation of a repressive nuclear compartment mediated by the long non-coding RNA Kcnq1ot1 initiated from imprinting centre 2 (IC2). However, it is unknown whether some maternally expressed genes are silenced on the paternal homologue via a Kcnq1ot1-independent mechanism. We have previously reported that maternal inheritance of a large truncation of Chr7 encompassing the entire IC2-regulated domain (DelTel7 allele) leads to embryonic lethality at mid-gestation accompanied by severe placental abnormalities. Kcnq1ot1 expression can be abolished on the paternal chromosome by deleting IC2 (IC2KO allele). When the IC2KO mutation is paternally inherited, epigenetic silencing is lost in the region and the DelTel7 lethality is rescued in compound heterozygotes, leading to viable DelTel7/IC2KO mice. RESULTS: Considering the important functions of several IC2-regulated genes in placentation, we set out to determine whether these DelTel7/IC2KO rescued conceptuses develop normal placentae. We report no abnormalities with respect to the architecture and vasculature of the DelTel7/IC2KO rescued placentae. Imprinted expression of several of the IC2-regulated genes critical to placentation is also faithfully recapitulated in DelTel7/IC2KO placentae. CONCLUSION: Taken together, our results demonstrate that all the distal chromosome 7 imprinted genes implicated in placental function are silenced by IC2 and Kcnq1ot1 on the paternal allele. Furthermore, our results demonstrate that the methylated maternal IC2 is not required for the regulation of nearby genes. The results show the potential for fully rescuing LQ trans placental abnormalities that are caused by imprinting defects.

[The Wiedemann-Beckwith syndrome. Its natural history and levels of prevention]. / El síndrome de Wiedemann-Beckwith. Su historia natural y sus niveles de prevención.

We attempted here the delineation of the natural history of the disease and corresponding prevention levels (NHD and PL) of the Wiedemann-Beckwith syndrome according to the classical model of Leavell and Clark for infectious-contagious diseases. This proposal was based on our own series of 39 patients and our previous reports on the didactics of the NHD and PL model, as well as on the relevant literature; with this approach we obtained an useful model which includes the health-disease status, the analysis of risk factors and the integration of the clinical practice with socio-epidemiological medicine. Furthermore, the NHD and PL model allow the selection of the preventive management depending on the clinical stage, namely health or disease. This approach to a Mendelian condition emphasizes that the Leavell and Clark concepts can be advantageously applied to any genetic disease.

[Subjective theories of illness as objective for genetic counselling-the Wiedemann-Beckwith-syndrome as example]. / Subjektive Krankheitstheorien als Gegenstand der genetischen Beratung am Beispiel des Wiedemann-Beckwith-Syndroms.

Genetic counselling deals with illness. Often, an "objective" theory of illness is presented, which is put into a subjective theory by the client. As an example, interviews with parents of children who have a Wiedemann-Beckwith-Syndrome are analysed. It can be shown that generating a subjective theory of illness is strongly connected with the experiencing of the illness. Thus, parents assess the Syndrome of their child quite differently and construct specific subjective theories about it. Especially assumptions about the cause of the illness differ.

El síndrome de Wiedemann Beckwith. Su historia natural y sus niveles de prevención / The Wiedemann Beckwith syndrome. Natural history and its levels of prevention

Nuestro objetivo principal es el de delinear la historia natural de la enfermedad y sus niveles de prevención (HNE y NP) en el síndrome de Wiedemann-Beckwith, tal como Leavell y Clark los diseñaron para los padecimiento infectocontagiosos. Para ello nos basamos en nuestra experiencia previa de 39 casos y en otros reportes propios relacionados con la didáctica de la HEN y NP, así como lo reportado en la literatura. Se obtiene con esto un modelo en el que se estudia el estado salud-enfermedad, se analizan los factores de riesgo, se une la medicina clínica con la medicina epidemiológica y social, y por otro lado, al estructurar la HNE y NP, nos permite actuar con medidas preventivas dependiendo de la ubicación de la fase, rígase salud o enfermedad. Es posible entonces que así como este padecimiento genético mendeliano se analiza bajo la HNE y NP, cualqluier otro de la misma etiología puede encuadrar en este modelo que resulta preferible al método tradicional