International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 2 - A FUNCTIONAL GENOMICS APPROACH TO THE INVESTIGATION OF HUMAN 6P GENE FUNCTION

Arkell R 1, Bogani D 1, Kuar K 2, Davies J 1, Mirza G 2, Willoughby C 1, McKeone R 1, Denny P 1, Ragoussis J 21 Mammalian Genetics Unit, Oxfordshire, United Kingdom, 2 Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

The telomeric region of human 6p contains genes required for many aspects of embryonic development.  Monozygosity for this region is associated with a variety of congenital abnormalities that include orofacial clefting and other craniofacial defects, CNS defects, eye abnormalities, ear abnormalities and deafness, heart, kidney and limb defects.  We have used functional genomics to generate mouse models that identify the 6p genes involved in the development of these structures.  To achieve this, we have taken advantage of a large region of synteny between human 6p and the proximal portion of mouse chromosome 13.  Mice monozygous for a region of chromosome 13 (corresponding to 6p25 and 6p22) are viable and fertile and replicate features of the human 6p deletion syndromes.  In addition, homozygous loss of function of the Foxq1 gene that resides within the deleted material produces mice with a glossy coat.  This has enabled a two-generation region specific screen for recessive, ENU induced mutations to be carried out.  Screening of 1729 pedigrees has identified 11 heritable mutations that are linked to Foxq1.  All of the mutations are embryonic lethal and phenotypes include clefting and other craniofacial defects, holoprosencephaly, heart, kidney and lung defects.  Recombination mapping has been used to further refine the location of the mutations within the deleted area and mutation detection in candidate genes is underway for the majority of the mutant lines.  The location and or identity of the mutated genes and associated phenotypes will be discussed with reference to the human 6p deletion syndromes.

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