Beckwith-Wiedemann syndrome (BWS; MIM 130650) is a complex congenital overgrowth disorder that occurs in approximately 1/13,700 live births. A diagnosis of BWS is usually based on the presence of two out of five major characteristics in the infant: macrosomia

814 INTRODUCTION Beckwith-Wiedemann syndrome (BWS; MIM 130650) is a complex congenital overgrowth disorder that occurs in approximately 1/13,700 live births. A diagnosis of BWS is usually based on the presence of two out of five major characteristics in the infant: macrosomia (birth weight >97th percentile), macroglossia, neonatal hypoglycaemia, ear creases or pits and/or abdominal wall defects. BWS can include other features such as hemihypertrophy, visceromegaly, hepatoblastoma, embryonal tumours, nevus flammeus, cleft palate, cardiac abnormalities, advanced bone age, enlarged placenta and abnormalities in placental vasculature (Weksberg et al., 2010). There is a high incidence of premature birth for BWS infants, sometimes in combination with polyhydramnios and gestational hypertension (Wangler et al., 2005), with some BWS mother’s suffering the more serious complication of HELLP and preeclampsia (Romanelli et al., 2009). BWS patients display multiple genetic and epigenetic mutations that mainly disrupt the expression of a cluster of imprinted genes located at human chromosome 11p15 (Cooper et al., 2005; Weksberg et al., 2005). Nearly half of patients with familial BWS carry germline mutations in the coding sequence of the maternally expressed cyclin-dependent kinase inhibitor 1c (CDKN1C; p57KIP2) gene (Hatada et al., 1996; Hatada et al., 1997; Lee et al., 1997; O’Keefe et al., 1997; Engel et al., 2000). However, BWS is predominantly seen as a sporadic occurrence and, in this group of patients, direct DNA mutations within CDKN1C mutations are relatively infrequent (<5%) (Cooper et al., 2005). The most frequent alteration in BWS, reported in >50% of patients, is loss of DNA methylation at the promoter of a long, non-coding RNA, KCNQ1OT (also known as LIT1), which lies 220 kb distant to CDKN1C. Loss of methylation of this region is associated with downregulation of CDKN1C (Diaz-Meyer et al., 2003). Studies on the corresponding mouse imprinted domain on distal chromosome 7 demonstrate that this region, termed KvDMR1 or IC2 (imprinting centre 2), acts as the imprinting centre for Cdkn1c (Caspary et al., 1998; Feinberg, 2000; Fitzpatrick et al., 2002). All these data suggest that loss of CDKN1C is a factor in the majority of BWS cases. However, although three independent studies examining loss of Cdkn1c function in mice identified several developmental abnormalities consistent with BWS, including abdominal wall defects, cleft palate, placentomegaly, renal dysplasia, adrenal cytomegaly, maternal preeclampsia and prematurity, none reported the cardinal feature of BWS, that of somatic overgrowth at birth (Yan et al., 1997; Zhang et al., 1997; Takahashi et al., 2000a; Takahashi et al., 2000b; Kanayama et al., 2002). In mice, Cdkn1c is expressed in derivatives of all three germ layers – the endoderm, mesoderm and ectoderm – and in all major organs of the body during embryonic development (Lee et al., 1995; Matsuoka et al., 1995; Westbury et al., 2001). Cdkn1c is primarily expressed in cells that are exiting cell cycle but are not terminally differentiated. In extraembryonic tissues, Cdkn1c is dynamically expressed during mid-to-late placental development in the giant trophoblast cells that abut the maternal decidua, the glycogen cells within the junctional zone, the fetal endothelium, the syncytiotrophoblast and some larger sinusoidal nuclei (Riley et al., 1998; Westbury et al., 2001; Georgiades et al., 2002; Coan et al., 2006). The spatial and temporal expression profile of Cdkn1c probably reflects the multiple functional roles that Cdkn1c plays during development. Cdkn1c, also known as p57Kip2, encodes a cyclin-dependant kinase inhibitor (CDKi) belonging to the same family as Cdkn1a (encoding p21) and Cdkn1b (encoding p27) (Hatada and Mukai, 1995; Lee et al., 1995; Matsuoka et al., 1995; Disease Models & Mechanisms 4, 814-821 (2011) doi:10.1242/dmm.007328