Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637, Poznan, Poland.
Department of Reproduction and Clinic of Farm Animals, Wroclaw University of Environmental and Life Sciences, Plac Grunwaldzki 49, 50-366, Wroclaw, Poland.
Anim Genet. 2019 Dec;50(6):705-711. doi: 10.1111/age.12850. Epub 2019 Sep 2.
The genetic background of disorders of sex development (DSD) in dogs with a normal male sex chromosome set (78,XY) is poorly described. In this study, we present for the first time, an analysis of six genes of the testosterone pathway, encoding enzymes (CYP17A1, HSD3B2, HSD17B3, SRD5A2) and transcription factors (NR5A1, AR). The entire coding sequence and flanking regions of the introns, 5'-UTR and 3'-UTR were analyzed in five DSD dogs (78,XY, SRY-positive) with ambiguous external genitalia and in 15 control dogs. A homozygous deletion of 2 bp in exon 2 of HSD17B3 (hydroxysteroid 17-beta dehydrogenase 3) was found in a Dachshund dog with enlarged clitoris, vulva and abdominal gonads and decreased serum testosterone level. In silico analysis revealed that this deleterious variant causes truncation of the encoded polypeptide (from 306 to 65 amino acids) and deprivation of the active site of the encoded enzyme. Genotyping of 23 control Dachshund dogs showed a normal homozygous genotype. Thus, we assumed that the 2-bp deletion is the causative variant. Moreover, 24 SNPs (four in CYP17A1, three in HSD3B2, six in HSD17B3, five in SRD5A2, one in AR and five in NR5A1), two intronic indels (one in HSD3B2 and one in SRD5A2) and two microsatellite polymorphisms in exon 1 of AR were found. Six SNPs appeared to be novel. No association with DSD phenotype was observed. Identification of the first case of DSD in domestic animals caused by a deleterious variant of a gene involved in testosterone synthesis showed that these genes are important candidates in such studies.
犬的性发育障碍（DSD）的遗传背景在正常雄性性染色体组（78,XY）中描述甚少。本研究首次分析了编码酶（CYP17A1、HSD3B2、HSD17B3、SRD5A2）和转录因子（NR5A1、AR）的睾酮途径的六个基因。在 5 只外生殖器模糊的 DSD 犬（78,XY，SRY 阳性）和 15 只对照犬中，分析了整个编码序列及其侧翼区域、内含子 5'-UTR 和 3'-UTR。在一只具有增大的阴蒂、外阴和腹部性腺以及降低的血清睾酮水平的达克斯猎犬中，发现 HSD17B3（羟固醇 17-β脱氢酶 3）外显子 2 中的 2bp 纯合缺失。计算机分析表明，这种有害的变异导致编码多肽的截断（从 306 个到 65 个氨基酸）和编码酶的活性位点缺失。对 23 只正常达克斯猎犬的基因分型显示出正常的纯合基因型。因此，我们假设 2bp 缺失是致病变异。此外，还发现了 24 个 SNP（CYP17A1 中有四个，HSD3B2 中有三个，HSD17B3 中有六个，SRD5A2 中有五个，AR 中有一个，NR5A1 中有五个），两个内含子插入缺失（HSD3B2 和 SRD5A2 各一个）和 AR 外显子 1 中的两个微卫星多态性。其中 6 个 SNP 似乎是新的。未观察到与 DSD 表型相关。首次在犬科动物中发现由参与睾酮合成的基因的有害变异引起的 DSD 病例，表明这些基因是此类研究的重要候选基因。
