Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome

Abstract

Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome.

Keywords: Brain abnormalities; Cornelia de Lange syndrome; Wnt pathway.

Fig. 1

Wnt genes expression during the brain developmental process, from gastrulation to the differentiation of the structures forming the central nervous system. Note the spatial and temporal overlapping of the gene expression pattern

Fig. 2

Example of brain abnormalities in a fetus at 25 weeks of gestation. Note the size reduction of the cerebellum with severe volume loss; the immaturity of sulcal pattern with slight underdevelopment of the frontal operculae for the gestational age, resulting in uncovering of the insula; the abnormalities of the corpus callosum that appears thin (in the trunk area) and short (with absence of the genu)

Fig. 3

Summary of the brain abnormalities in CdLS. Cartoons compare the sagittal section of normal brain (on the left) with the sagittal section of affected brain (on the right). In the same patient, often more than one of the presented brain abnormalities are present, however only seldom all lesions are detected in the same patient

Fig. 4

Diagram of link between CdLS, Wnt pathway and brain development. Possible link between molecular alterations and brain abnormalities in CdLS. An impairment in Wnt pathway leads to abnormalities in brain development during development that could represent one of the causes of CdLS brain malformations