Renal dysplasia in Leonberger dogs – An emerging recessive congenital disorder?

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Anna Letko, Corinne Gurtner, Vidhya Jagannathan, Cord Drögemüller
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Leonbergers globally suffer from various diseases, with cancer, orthopedic and neurological conditions being the most frequent (Letko et al., <span>2020</span>). However, in the owner-reported health survey, 0.44% of dogs were diagnosed with ‘renal system issues’ (Letko et al., <span>2020</span>). The underlying cause of RD has not yet been described in this breed.</p><p>In a litter of eight purebred Leonbergers, one puppy was diagnosed with a congenital form of RD and euthanised at 11 weeks of age owing to worsening clinical signs. For diagnosis confirmation and histopathological examination, the kidneys were collected and fixed in 10% buffered formalin and embedded in paraffin. Sections of 1.5 μm were cut and compared with a kidney sample of a control dog (Figure 1a). Histological lesions were present in both kidneys. The cortex and medulla had areas of fetal glomeruli featuring small glomeruli with peripheral nuclei and inapparent capillaries. 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引用次数: 0

Abstract

Renal dysplasia (RD) is a complex congenital disease characterised by abnormal differentiation of renal tissue (Greco, 2001). Several forms of inherited RD have been reported in various animal species, including dogs (OMIA:001135-9615). The canine RD phenotype can range from asymptomatic to severe chronic kidney disease and the genetic etiology remains unclear (Cavalera et al., 2021; Dillard et al., 2018; Safra et al., 2015). Similar secondary kidney damage can also result from recessive metabolic disorders such as xanthinuria, known in dogs (OMIA:001283-9615) or cattle (OMIA:001283-9913). Leonbergers globally suffer from various diseases, with cancer, orthopedic and neurological conditions being the most frequent (Letko et al., 2020). However, in the owner-reported health survey, 0.44% of dogs were diagnosed with ‘renal system issues’ (Letko et al., 2020). The underlying cause of RD has not yet been described in this breed.

In a litter of eight purebred Leonbergers, one puppy was diagnosed with a congenital form of RD and euthanised at 11 weeks of age owing to worsening clinical signs. For diagnosis confirmation and histopathological examination, the kidneys were collected and fixed in 10% buffered formalin and embedded in paraffin. Sections of 1.5 μm were cut and compared with a kidney sample of a control dog (Figure 1a). Histological lesions were present in both kidneys. The cortex and medulla had areas of fetal glomeruli featuring small glomeruli with peripheral nuclei and inapparent capillaries. Some tubuli appeared small and immature and were lined by closely packed cuboidal epithelial cells while others were ectatic and sometimes contained birefringent greenish crystals and occasional mineralisation. Additionally, some tubuli contained intraluminal eosinophilic droplet material. The interstitium showed multifocal areas with mild fibrosis and aggregates of lymphocytes, plasma cells, a few neutrophils and macrophages, some of which were laden with hemosiderin (Figure 1b).

Samples for genome sequencing of the affected dog or his littermates were not available. Therefore, parental whole-genome sequencing (WGS) data were utilised to gain insights into the genetic basis of RD. Blood samples and the DNA of the unaffected dam and sire of the case were previously donated to the Vetsuisse Biobank for diagnostic purposes. Whole-genome sequencing was performed at ~20× read depth using Illumina NovaSeq6000 and variants were called as described previously (Letko et al., 2023). The pedigree records supported a recessive mode of inheritance (Figure S1). Therefore, the WGS data were queried for variants heterozygous in both parents with respect to canine reference UU_Cfam_GSD_1.0. A global cohort of 1541 dogs, including 85 unrelated adult Leonbergers not known to be RD affected (Table S1), was used to evaluate allele frequency of the 1 090 859 shared variants. Based on the impact predicted by snpeff v5.0e, considering no homozygotes among control dogs, and an allele frequency below 1% in other breeds, 29 protein-coding (only 16 of these variants affected genes with human orthologues) and 1106 non-coding variants were left (Table S2). Although no protein-changing variant was present in an obvious RD candidate gene, three were prioritised as warranting further investigation: a splice site variant in SLC15A2 known to be associated with renal protein reabsorption (Rubio-Aliaga et al., 2003), a missense variant in SPOCK2 that influences risk of end-stage kidney disease (Ngo et al., 2020) and a missense variant in TRABD2B that is implicated in organogenesis through the Wnt-signaling pathway with high expression in kidney (Reis et al., 2014).

This study presents the first histopathological description of RD in a purebred Leonberger and offers a list of putative pathogenic variants potentially contributing to the disease phenotype based on parental WGS. However, samples of RD-affected Leonberger dogs and of healthy controls are essential to find the causal variant(s) and decrease the occurrence of RD in this breed.

Anna Letko: Conceptualization; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. Corinne Gurtner: Investigation; methodology; visualization; writing – original draft; writing – review and editing. Vidhya Jagannathan: Data curation; software. Cord Drögemüller: Funding acquisition; project administration; resources; writing – review and editing.

The authors declare no conflicts of interest.

The dogs in this study were privately owned and samples were collected with the consent of their owners for diagnostic reasons and did not constitute an animal experiment.

Abstract Image

莱昂伯格犬肾发育不良--一种新出现的隐性先天性疾病?
肾发育不良(RD)是一种复杂的先天性疾病,其特点是肾组织分化异常(Greco,2001 年)。据报道,在包括犬在内的各种动物物种中,存在多种形式的遗传性 RD(OMIA:001135-9615)。犬 RD 表型可从无症状到严重慢性肾病不等,其遗传病因仍不清楚(Cavalera 等人,2021 年;Dillard 等人,2018 年;Safra 等人,2015 年)。狗(OMIA:001283-9615)或牛(OMIA:001283-9913)的黄嘌呤尿症等隐性代谢性疾病也会导致类似的继发性肾损伤。全球的莱昂伯格犬都患有各种疾病,其中癌症、骨科和神经系统疾病最为常见(Letko 等人,2020 年)。然而,在主人报告的健康调查中,0.44% 的狗狗被诊断出患有 "肾脏系统疾病"(Letko 等人,2020 年)。在一窝 8 只纯种莱昂伯格犬中,有一只幼犬被诊断出患有先天性 RD,并在 11 周大时因临床症状恶化而被安乐死。为了确诊和进行组织病理学检查,采集了肾脏,用 10% 缓冲福尔马林固定,并用石蜡包埋。切取 1.5 μm 的切片,并与对照狗的肾脏样本进行比较(图 1a)。两个肾脏都出现了组织学病变。皮质和髓质有胎儿肾小球区域,其特点是肾小球较小,周边有核,毛细血管不明显。一些肾小管看起来小而不成熟,内衬是紧密排列的立方体上皮细胞,而另一些肾小管则是异位的,有时含有双折射的绿色晶体,偶尔还有矿化现象。此外,一些肾小管内含有嗜酸性液滴物质。间质表现为多灶性轻度纤维化以及淋巴细胞、浆细胞、少量中性粒细胞和巨噬细胞的聚集,其中一些聚集有血色素(图 1b)。(a) 与之无关的对照组(10 周大的雄性圣伯纳犬,死于害虫性肺炎)的肾脏进行对比,显示肾小球发育成熟(白色箭头)。(b)患病犬的肾脏,显示胎儿肾小球(黑色箭头)和间质纤维化(星号)。血色素和伊红染色,放大 40 倍。因此,我们利用亲代全基因组测序(WGS)数据来了解 RD 的遗传基础。病例中未受影响的母犬和父犬的血样和 DNA 已捐献给 Vetsuisse 生物库,用于诊断。全基因组测序使用 Illumina NovaSeq6000 以 ~20× 读取深度进行,变异的调用方法如前所述(Letko 等人,2023 年)。血统记录支持隐性遗传模式(图 S1)。因此,对 WGS 数据进行了查询,以寻找与犬参考 UU_Cfam_GSD_1.0 相对应的父母双方的杂合变异。全球共有 1541 只狗,其中包括 85 只没有血缘关系的成年莱昂伯格犬,但不知道它们是否受 RD 影响(表 S1),用于评估 1 090 859 个共享变异的等位基因频率。根据 snpeff v5.0e 预测的影响,考虑到对照犬中没有同源变异体,以及其他犬种的等位基因频率低于 1%,剩下 29 个编码蛋白变异体(其中只有 16 个变异体影响到与人类同源的基因)和 1106 个非编码变异体(表 S2)。虽然在明显的 RD 候选基因中没有出现改变蛋白质的变异,但有三个变异被认为值得进一步研究:SLC15A2 的剪接位点变异,已知与肾脏蛋白质重吸收有关(Rubio-Aliaga 等人,2003 年);SPOCK2 的错义变异,影响终末期肾病的风险(Ngo 等人,2020 年);以及一个错义变异、本研究首次对纯种莱昂伯格犬的 RD 进行了组织病理学描述,并基于亲本 WGS 列出了可能导致疾病表型的潜在致病变体。然而,要找到致病变异体并减少该犬种中 RD 的发生,必须采集受 RD 影响的莱昂伯格犬和健康对照组的样本。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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