Mapping and Phenotyping Genes in the Del(13)Svea36H Region of Mouse Chromosome 13

McKeone, Richard (2009). Mapping and Phenotyping Genes in the Del(13)Svea36H Region of Mouse Chromosome 13. PhD thesis The Open University.



Del(13)Svea36H (also known as Del36H) is a 12.7Mb gene-rich region that has been deleted in mouse chromosome 13. It contains numerous disease loci as well as showing conserved synteny to two regions of human chromosome 6p which can be missing in some deletion syndromes. The mouse deletion causes homozygous embryonic lethality but is hemizygously viable. It has therefore been used as a tool to screen for lethal recessive mutations that could help to identify developmental genes that are responsible for the symptoms of the associated human diseases.

A Physical map of the region was constructed in order to facilitate the mapping of mutations arising from the lethal screen. Eleven lethal lines have been mapped to varying degrees of accuracy, including one lethal mutation that exhibited circulation defects which localised to Sox4.

The forkhead transcription factor Foxf2 was considered a potential candidate for embryonic lethal mutations within the interval. To complement the lethal recessive screen, an attempt was made to identify an allelic series of mutations in the gene. ENU mutagenised mouse archives were screened for novel Foxf2 mutations. Three potential functional mutations were discovered - two coding mutations (Foxf2W174R and Foxf2V412F), and a splice site mutation.

Foxf2W174R heterozygotes exhibited thinning of the iris stroma, alongside hypoplasia of the trabecular meshwork and canal of Schlemm and a reduction in the iridocorneal angle. Homozygote eyes at E18.5 show no signs of the developing ciliary body which were seen in wildtype littermates.

Homozygote carriers survive for several days, significantly longer than the 18hr survival time observed in the knockout, suggesting a hypomorphic mutation. In contrast to Foxf2 knockouts, homozygotes for the W174R mutation do not possess a cleft palate or malformed tongue.

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