Positional cloning of the GCT1 granulosa cell tumor susceptibilty locus in swr inbred mice

Smith, Kerri Nicole (2011) Positional cloning of the GCT1 granulosa cell tumor susceptibilty locus in swr inbred mice. Masters thesis, Memorial University of Newfoundland.

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Abstract

Female mice of the SWR/Bm (SWR) inbred strain are susceptible to the spontaneous initiation of juvenile-onset granulosa cell (GC) tumours of the ovary at the onset of puberty. The mouse GC tumours share histological, endocrinological and malignant features with juvenile-type GC tumours found in infants and young girls, and thus the SWR strain represents a model system for the identification of susceptibility genes. Genetic mapping studies between the SWR strain and tumour-resistant strains have consistently associated the Granulosa cell tumour susceptibility 1 (Gct1) locus on distal mouse chromosome (Chr) 4 with the GC tumour phenotype. Mapping the trait for dehydroepiandrosterone (DHEA) induced GC tumour appearance in six congenic mouse sublines successfully resolved the Gct1 locus to 1.51 Mb and a candidate list of 23 unique annotated protein coding genes, non-coding RNA genes, and other processed transcripts with may represent novel genes with biological activity. A qualitative assessment of prioritized genes within the refined Gct1 interval did not exclude any from the ovarian compartment and therefore shared identity with Gct1. Tnfrsf1b was given top priority as a candidate gene given its described role in ovarian biology, but no conclusive sequence variation or expression differences unique so SWR were identified that indicated Tnfrsf1b is Gct1. Three other protein coding genes (Dhrs3, Tnfrst8, and Vps13d) are present in the Gct1 region and orthologous between mouse and human, and are promising candidates for Gct1.

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