School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Camperdown, NSW, 2006, Australia.
Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Camperdown, NSW, 2006, Australia.
Sci Rep. 2020 Oct 26;10(1):18223. doi: 10.1038/s41598-020-75243-x.
Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (P = 2.87E) was discovered and validated in a closely related population (P = 1.75E). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.
先天性代谢错误是一种遗传疾病，可破坏中间代谢途径，并导致膳食营养素吸收和代谢缺陷。在澳大利亚牧羊犬的繁殖群体中，有 17 只小狗出现肠道脂质吸收不良。幼年犬表现出出生后生长迟缓、脂肪泻、腹胀和毛发粗糙。通过全基因组关联分析，在一个密切相关的群体中发现了与 CFA28 相关的位点（P=2.87E）并得到了验证（P=1.75E）。在 CFA28 上发现了一个 103.3kb 的缺失 NC_006610.3CFA28:g.23380074_23483377del，其中包含酰基辅酶 A 合成酶长链家族成员 5（ACSL5）和锌指 DHHC 型包含 6（ZDHHC6）基因，使用全转录组数据进行了特征描述。全转录组测序显示，受影响的牧羊犬空肠组织中 ACSL5 基因无表达且 ZDHHC6 基因剪接中断。ACSL5 基因在长链脂肪酸吸收中起关键作用，在我们受影响的牧羊犬中观察到的表型类似于敲除小鼠模型。开发了一种基于 PCR 的诊断测试，并证实了常染色体隐性完全外显率的遗传模式。我们得出结论，导致 ACSL5 基因缺失的结构变异很可能是澳大利亚牧羊犬肠道脂质吸收不良的原因。
