A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats

Danielle Aberdein, John Munday, Barbara Gandolfi, Keren Dittmer, Richard Malik, Dorian Garrick, Leslie Lyons, 99 Lives Consortium

Research output: Contribution to journalArticle

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Abstract

British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.
Original languageEnglish
Pages (from-to)47-55
Number of pages9
JournalMammalian Genome
Volume28
Issue number1
DOIs
Publication statusPublished - 2017

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Autoimmune Lymphoproliferative Syndrome
Cats
Ligands
Genome
Apoptosis
Inbreeding
Nonsense Codon
Adenine
Exons
Lymphocytes

Cite this

Aberdein, D., Munday, J., Gandolfi, B., Dittmer, K., Malik, R., Garrick, D., ... Consortium, . L. (2017). A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. Mammalian Genome, 28(1), 47-55. https://doi.org/10.1007/s00335-016-9668-1
Aberdein, Danielle ; Munday, John ; Gandolfi, Barbara ; Dittmer, Keren ; Malik, Richard ; Garrick, Dorian ; Lyons, Leslie ; Consortium, 99 Lives. / A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. In: Mammalian Genome. 2017 ; Vol. 28, No. 1. pp. 47-55.
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abstract = "British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.",
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Aberdein, D, Munday, J, Gandolfi, B, Dittmer, K, Malik, R, Garrick, D, Lyons, L & Consortium, L 2017, 'A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats', Mammalian Genome, vol. 28, no. 1, pp. 47-55. https://doi.org/10.1007/s00335-016-9668-1

A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. / Aberdein, Danielle ; Munday, John ; Gandolfi, Barbara; Dittmer, Keren; Malik, Richard; Garrick, Dorian; Lyons, Leslie; Consortium, 99 Lives.

In: Mammalian Genome, Vol. 28, No. 1, 2017, p. 47-55.

Research output: Contribution to journalArticle

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T1 - A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats

AU - Aberdein, Danielle

AU - Munday, John

AU - Gandolfi, Barbara

AU - Dittmer, Keren

AU - Malik, Richard

AU - Garrick, Dorian

AU - Lyons, Leslie

AU - Consortium, 99 Lives

PY - 2017

Y1 - 2017

N2 - British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.

AB - British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.

KW - Syndrome ALPS

KW - Mutation

KW - disease

KW - apoptosis

KW - dominant

KW - patient

KW - genome

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