LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa.
LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa.
复制标题
DOI：
10.3390/genes11091055
复制
发表时间：
2020-09-07
期刊：
影响因子：
3.5
通讯作者：
Leeb T
中科院分区：
文献类型：
--
作者：
Kiener S;Laprais A;Mauldin EA;Jagannathan V;Olivry T;Leeb T
在一个高度近亲繁殖的澳大利亚牧羊犬窝中，五只幼犬中有三只在出生后的头几周内出现皮肤、脚垫和口腔粘膜的广泛溃疡。组织学检查显示表皮从基底膜内或仅在基底膜下方的下层真皮裂开，这导致了常染色体隐性遗传的交界性大疱性表皮病（JEB）的初步诊断。一只受影响犬的内镜检查也显示胃肠道上皮和下层组织分离。由于临床体征的严重程度，必须对所有3只犬实施人道处死。我们对一只受影响的小狗的基因组进行了测序，并将数据与73个对照基因组进行了比较。在37个已知的皮肤脆性表型候选基因中搜索私人变体，发现了一个单一的蛋白质变化变体LAMB 3：c.1174T>C或p.Cys392Arg。预测该变体改变异源三聚体层粘连蛋白-322的层粘连蛋白β3亚基中的保守半胱氨酸，其介导表皮基底膜与下层真皮的结合。人类LAMB 3基因的功能丧失变异导致隐性形式的JEB。我们证实了预期的共分离的基因型在澳大利亚牧羊犬的家庭。突变等位基因在两个基因分型的情况下是纯合子和杂合子在三个未受影响的近亲。在澳大利亚牧羊犬品种的其他242个对照组中没有发现，在其他600多个对照组中也没有发现。这些数据表明LAMB 3：c.1174T>C代表致病变体。据我们所知，这项研究代表了LAMB 3相关的JEB在家畜中的第一份报告。
In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.
登录
查看更多内容
影响因子：
3.5
作者：
Baldeschi, C;Gache, Y;Meneguzzi, G
通讯作者：
Meneguzzi, G
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
6.9
作者：
Has, Cristina;Nystroem, Alexander;Uitto, Jouni
通讯作者：
Uitto, Jouni
影响因子：
2.4
作者：
Jagannathan, V;Droegemueller, C.;Wade, Claire
通讯作者：
Wade, Claire
影响因子：
3.7
作者：
Niskanen J;Dillard K;Arumilli M;Salmela E;Anttila M;Lohi H;Hytönen MK
通讯作者：
Hytönen MK