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

Danielle Aberdein, John S. Munday, Barbara Gandolfi, Keren E. Dittmer, Richard Malik, Dorian J. Garrick, Leslie A. Lyons, Lives Consortium 99 Lives Consortium, Pauol C. Alves, Gregory S. Barsh, Holly C. Beale, Adam R. Boyko, Marta G. Castelhano, Patricia Chan, N. Matthew Ellinwood, Christopher R. Helps, Christopher B. Kaelin, Tosso Leeb, Hannes Lohi, Maria Longeri & 8 others Michael J. Montague, William J. Murphy, Niels C. Pedersen, Max F. Rothschild, William F. Swanson, Karen A. Terio, Rory J. Todhunter, Wesley C. Warren

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)47-55
Number of pages9
JournalMammalian Genome
Volume28
Issue number1-2
DOIs
StatePublished - Feb 1 2017

Fingerprint

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

ASJC Scopus subject areas

  • Genetics

Cite this

Aberdein, D., Munday, J. S., Gandolfi, B., Dittmer, K. E., Malik, R., Garrick, D. J., ... Warren, W. C. (2017). A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. Mammalian Genome, 28(1-2), 47-55. DOI: 10.1007/s00335-016-9668-1

A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. / Aberdein, Danielle; Munday, John S.; Gandolfi, Barbara; Dittmer, Keren E.; Malik, Richard; Garrick, Dorian J.; Lyons, Leslie A.; 99 Lives Consortium, Lives Consortium; Alves, Pauol C.; Barsh, Gregory S.; Beale, Holly C.; Boyko, Adam R.; Castelhano, Marta G.; Chan, Patricia; Ellinwood, N. Matthew; Helps, Christopher R.; Kaelin, Christopher B.; Leeb, Tosso; Lohi, Hannes; Longeri, Maria; Montague, Michael J.; Murphy, William J.; Pedersen, Niels C.; Rothschild, Max F.; Swanson, William F.; Terio, Karen A.; Todhunter, Rory J.; Warren, Wesley C.

In: Mammalian Genome, Vol. 28, No. 1-2, 01.02.2017, p. 47-55.

Research output: Contribution to journalArticle

Aberdein, D, Munday, JS, Gandolfi, B, Dittmer, KE, Malik, R, Garrick, DJ, Lyons, LA, 99 Lives Consortium, LC, Alves, PC, Barsh, GS, Beale, HC, Boyko, AR, Castelhano, MG, Chan, P, Ellinwood, NM, Helps, CR, Kaelin, CB, Leeb, T, Lohi, H, Longeri, M, Montague, MJ, Murphy, WJ, Pedersen, NC, Rothschild, MF, Swanson, WF, Terio, KA, Todhunter, RJ & Warren, WC 2017, 'A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats' Mammalian Genome, vol 28, no. 1-2, pp. 47-55. DOI: 10.1007/s00335-016-9668-1
Aberdein D, Munday JS, Gandolfi B, Dittmer KE, Malik R, Garrick DJ et al. A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. Mammalian Genome. 2017 Feb 1;28(1-2):47-55. Available from, DOI: 10.1007/s00335-016-9668-1

Aberdein, Danielle; Munday, John S.; Gandolfi, Barbara; Dittmer, Keren E.; Malik, Richard; Garrick, Dorian J.; Lyons, Leslie A.; 99 Lives Consortium, Lives Consortium; Alves, Pauol C.; Barsh, Gregory S.; Beale, Holly C.; Boyko, Adam R.; Castelhano, Marta G.; Chan, Patricia; Ellinwood, N. Matthew; Helps, Christopher R.; Kaelin, Christopher B.; Leeb, Tosso; Lohi, Hannes; Longeri, Maria; Montague, Michael J.; Murphy, William J.; Pedersen, Niels C.; Rothschild, Max F.; Swanson, William F.; Terio, Karen A.; Todhunter, Rory J.; Warren, Wesley C. / A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats.

In: Mammalian Genome, Vol. 28, No. 1-2, 01.02.2017, p. 47-55.

Research output: Contribution to journalArticle

@article{843f7d03682c4d55be9924dfff24db3b,
title = "A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats",
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.",
author = "Danielle Aberdein and Munday, {John S.} and Barbara Gandolfi and Dittmer, {Keren E.} and Richard Malik and Garrick, {Dorian J.} and Lyons, {Leslie A.} and {99 Lives Consortium}, {Lives Consortium} and Alves, {Pauol C.} and Barsh, {Gregory S.} and Beale, {Holly C.} and Boyko, {Adam R.} and Castelhano, {Marta G.} and Patricia Chan and Ellinwood, {N. Matthew} and Helps, {Christopher R.} and Kaelin, {Christopher B.} and Tosso Leeb and Hannes Lohi and Maria Longeri and Montague, {Michael J.} and Murphy, {William J.} and Pedersen, {Niels C.} and Rothschild, {Max F.} and Swanson, {William F.} and Terio, {Karen A.} and Todhunter, {Rory J.} and Warren, {Wesley C.}",
year = "2017",
month = "2",
doi = "10.1007/s00335-016-9668-1",
volume = "28",
pages = "47--55",
journal = "Mammalian Genome",
issn = "0938-8990",
publisher = "Springer New York",
number = "1-2",

}

TY - JOUR

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

AU - Aberdein,Danielle

AU - Munday,John S.

AU - Gandolfi,Barbara

AU - Dittmer,Keren E.

AU - Malik,Richard

AU - Garrick,Dorian J.

AU - Lyons,Leslie A.

AU - 99 Lives Consortium,Lives Consortium

AU - Alves,Pauol C.

AU - Barsh,Gregory S.

AU - Beale,Holly C.

AU - Boyko,Adam R.

AU - Castelhano,Marta G.

AU - Chan,Patricia

AU - Ellinwood,N. Matthew

AU - Helps,Christopher R.

AU - Kaelin,Christopher B.

AU - Leeb,Tosso

AU - Lohi,Hannes

AU - Longeri,Maria

AU - Montague,Michael J.

AU - Murphy,William J.

AU - Pedersen,Niels C.

AU - Rothschild,Max F.

AU - Swanson,William F.

AU - Terio,Karen A.

AU - Todhunter,Rory J.

AU - Warren,Wesley C.

PY - 2017/2/1

Y1 - 2017/2/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84992126344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992126344&partnerID=8YFLogxK

U2 - 10.1007/s00335-016-9668-1

DO - 10.1007/s00335-016-9668-1

M3 - Article

VL - 28

SP - 47

EP - 55

JO - Mammalian Genome

T2 - Mammalian Genome

JF - Mammalian Genome

SN - 0938-8990

IS - 1-2

ER -