Identification of a mutation associated with fatal Foal Immunodeficiency Syndrome in the Fell and Dales pony.
PLoS Genet
; 7(7): e1002133, 2011 Jul.
Article
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| MEDLINE
| ID: mdl-21750681
ABSTRACT
The Fell and Dales are rare native UK pony breeds at risk due to falling numbers, in-breeding, and inherited disease. Specifically, the lethal Mendelian recessive disease Foal Immunodeficiency Syndrome (FIS), which manifests as B-lymphocyte immunodeficiency and progressive anemia, is a substantial threat. A significant percentage (â¼10%) of the Fell ponies born each year dies from FIS, compromising the long-term survival of this breed. Moreover, the likely spread of FIS into other breeds is of major concern. Indeed, FIS was identified in the Dales pony, a related breed, during the course of this work. Using a stepwise approach comprising linkage and homozygosity mapping followed by haplotype analysis, we mapped the mutation using 14 FIS-affected, 17 obligate carriers, and 10 adults of unknown carrier status to a â¼1 Mb region (29.8 - 30.8 Mb) on chromosome (ECA) 26. A subsequent genome-wide association study identified two SNPs on ECA26 that showed genome-wide significance after Bonferroni correction for multiple testing BIEC2-692674 at 29.804 Mb and BIEC2-693138 at 32.19 Mb. The associated region spanned 2.6 Mb from â¼29.6 Mb to 32.2 Mb on ECA26. Re-sequencing of this region identified a mutation in the sodium/myo-inositol cotransporter gene (SLC5A3); this causes a P446L substitution in the protein. This gene plays a crucial role in the regulatory response to osmotic stress that is essential in many tissues including lymphoid tissues and during early embryonic development. We propose that the amino acid substitution we identify here alters the function of SLC5A3, leading to erythropoiesis failure and compromise of the immune system. FIS is of significant biological interest as it is unique and is caused by a gene not previously associated with a mammalian disease. Having identified the associated gene, we are now able to eradicate FIS from equine populations by informed selective breeding.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Simportadores
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Estudio de Asociación del Genoma Completo
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Caballos
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Síndromes de Inmunodeficiencia
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Mutación
Tipo de estudio:
Diagnostic_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
PLoS Genet
Asunto de la revista:
GENETICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Reino Unido