title: A mouse splice-site mutant and individuals with atypical chromosome 22q11.2 deletions demonstrate the crucial role for crkl in craniofacial and pharyngeal development.
abstract: The 22q11.2 deletion syndrome (22q11DS) is thought to be a contiguous gene syndrome caused by haploinsufficiency for a variable number of genes with overlapping function during the development of the craniofacial, pharyngeal and cardiac structures. The complexity of genetic and developmental anomalies resulting in 22q11DS has made attributing causation to specific genes difficult. The CRKL gene resides within the common 3-Mb region, most frequently affected in 22q11DS, and has been shown to play an essential role in the development of tissues affected in 22q11DS. Here, we report the characterisation of a mouse strain we named 'snoopy', harbouring a novel Crkl splice-site mutation that results in a loss of Crkl expression. The snoopy strain exhibits a variable phenotype that includes micrognathia, pharyngeal occlusion, aglossia and holoprosencephaly, and altered retinoic acid and endothelin signalling. Together, these features are reminiscent of malformations occurring in auriculocondylar syndrome and agnathia-otocephaly complex, 2 conditions not previously associated with the CRKL function. Comparison of the features of a cohort of patients harbouring small 22q11.2 deletions centred over the CRKL gene, but sparing TBX1, highlights the role of CRKL in contributing to the craniofacial features of 22q11DS. These analyses demonstrate the central role of Crkl in regulating signalling events in the developing oropharyngeal complex and its potential to contribute to dysmorphology.
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Miller
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Victorian Clinical Genetics Services, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: Megan F
authors.initials: MF
authors.lastname: Welfare
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Victorian Clinical Genetics Services, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: Susan M
authors.initials: SM
authors.lastname: White
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Victorian Clinical Genetics Services, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Victorian Clinical Genetics Services, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.affiliation: Victorian Clinical Genetics Services, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: Trent
authors.initials: T
authors.lastname: Burgess
authors.affiliation: Section of Oral and Maxillofacial Surgery, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Heggie
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Vic., Australia.
authors.forename: Georgina
authors.initials: G
authors.lastname: Caruana
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Vic., Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Bertram
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Vic., Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.affiliation: Murdoch Childrens Research Institute, Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Parkville, Vic., Australia ; Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Farlie
keywords: Craniofacial development; Crkl; Deletion 22q11.2; Malformation; Pharyngeal patterning