YPEL1 in craniofacial development and human disease

© 2010 Dr. Tiong Yang TanThe 22q11.2 chromosomal landscape predisposes to genomic rearrangements and a variety of clinical phenotypes. The most well known of these are the proximal 22q11.2 microdeletion and Cat eye syndromes (CES), but more recently other copy number abnormalities within the region have been recognised, especially with increased use of microarrays in the investigation of patients with congenital malformations or cognitive impairment. TBX1 mutations have also been found in some patients with phenotypes reminiscent of 22q11.2 syndromes. There is some phenotypic overlap between the different 22q11.2 syndromes, often with craniofacial, cardiac and cognitive involvement, but it is becoming increasingly clear that they are cytogenetically and clinically distinct. The inter- and intra-familial phenotypic variability of the 22q11.2 syndromes presents particular challenges in the prediction of clinical consequences following the diagnosis of a 22q11.2 copy number abnormality in the paediatric or prenatal setting. Our understanding of this phenotypic variability is limited, but recent studies of genes within the region and their interactions provide some insight into the pathogenesis of these syndromes, and suggest a possible common developmental pathway critical in embryonic morphogenesis. Here, the role of a distal 22q11.2 gene, YPEL1, in craniofacial development is investigated using in vitro and in vivo approaches in the avian model. Analysis of endogenous YPEL1 supports the notion that it plays a role in the development of structures derived from the pharyngeal arches and that it localises to the nucleus. Retroviral-mediated in vivo overexpression of YPEL1 causes abnormal mandibular and ocular morphogenesis associated with increased apoptosis, with several lines of evidence suggesting involvement of the BMP/MSX pathway. Detailed characterisation of the YPEL1-induced phenotypic abnormalities in chick include analyses of chondrocyte disorganisation, tissue proliferation and cell death and in vitro and in vivo expression of genes involved in craniofacial development. This work also describes the clinical and molecular characterisation of five families with copy number abnormalities affecting distal 22q11.2. Novel clinical features expand the phenotypic spectrum, including diaphragmatic hernia and Mullerian fusion anomalies associated with the distal microdeletion syndrome, and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. Additionally, the diagnosis of a distal 22q11.2 microdeletion in a patient with Goldenhar syndrome confirms that this region is a potential locus for this causally heterogeneous disorder. Clinical characterisation of the distal 22q11.2 families led to the investigation of two patient cohorts for distal 22q11.2 anomalies. In broad terms, the work presented herein examines the relationship between YPEL1 in avian craniofacial development and the developmental pathogenesis of the dysmorphology observed in the human distal 22q11.2 syndromes, Goldenhar syndrome and related phenotypes