Abstract
SUMMARYMutations in the imprinted CDKN1C gene are associated with the childhood developmental disorder Beckwith-Wiedemann syndrome (BWS). Multiple mouse models with deficiency of Cdkn1c recapitulate some aspects of BWS but do not exhibit overgrowth of the newborn, a cardinal feature of patients with BWS. In this study, we found that Cdkn1c mutants attained a 20% increase in weight during gestation but experienced a rapid reversal of this positive growth trajectory very late in gestation. We observed a marked effect on placental development concurrently with this loss of growth potential, with the appearance of large thrombotic lesions in the labyrinth zone. The trilaminar trophoblast layer that separates the maternal blood sinusoids from fetal capillaries was disordered with a loss of sinusoidal giant cells, suggesting a role for Cdkn1c in maintaining the integrity of the maternal-fetal interface. Furthermore, the overgrowth of mutant pups decreased in the face of increasing intrauterine competition, identifying a role for Cdkn1c in the allocation of the maternal resources via the placenta. This work explains one difficulty in precisely replicating BWS in this animal model: the differences in reproductive strategies between the multiparous mouse, in which intrauterine competition is high, and humans, in which singleton pregnancies are more common.
Highlights
Beckwith-Wiedemann syndrome (BWS; MIM 130650) is a complex congenital overgrowth disorder that occurs in approximately 1/13,700 live births
We found that the survival frequency of Cdkn1c mutant pups on the 129 background was similar to this, with four out of 60 survivors carrying the targeted allele (Table 1)
Reassessing the birth weights in existing BWS patients with known inactivating mutations in cyclin-dependent kinase inhibitor 1c (CDKN1C) and those that have an epigenetic mutation at KvDMR will be an important step forward in our understanding of the aetiology of BWS
Summary
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 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). 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). BWS is predominantly seen as a sporadic occurrence and, in this group of patients, direct DNA mutations within CDKN1C mutations are Received 29 November 2010; Accepted 18 May 2011
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