Aberdein Danielle, Munday John S, Gandolfi Barbara, Dittmer Keren E, Malik Richard, Garrick Dorian J, Lyons Leslie A
Pathobiology, Institute of Veterinary, Animal, and Biomedical Sciences, Massey University, Tennent Drive, Palmerston North, New Zealand.
Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO, 65211, USA.
Mamm Genome. 2017 Feb;28(1-2):47-55. doi: 10.1007/s00335-016-9668-1. Epub 2016 Oct 21.
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.
多窝英国短毛猫（BSH）幼猫死于一种严重的非肿瘤性淋巴细胞增殖性疾病，该疾病与人类自身免疫性淋巴细胞增殖综合征（ALPS）有许多相似之处。人类ALPS是由FAS介导的淋巴细胞凋亡的遗传缺陷引起的，因此研究了BSH猫是否存在类似缺陷。对两只患病幼猫的全基因组进行了测序，并与82个现有的猫基因组进行了比较。两只BSH幼猫在FAS配体基因的外显子3内都有腺嘌呤的纯合插入。由此产生的移码和过早的终止密码子预计会导致一种严重截短的蛋白质，这种蛋白质不太可能激活FAS。另外三只患病的BSH幼猫对该变体是纯合的，而16只未受影响但亲缘关系密切的BSH猫中有11只是该变体的杂合子。研究中的所有BSH猫都来自一个近亲繁殖严重的种群。在对510只非BSH猫的进一步调查中未发现该变体。FAS介导的凋亡途径中遗传缺陷的鉴定证实，BSH猫的淋巴细胞增殖性疾病符合人类ALPS的诊断标准。这些结果将有助于开发一种基因检测方法来检测BSH携带动物。
