PDF(Pubmed)
Abstract：
In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.
摘要：
在人类中,先天性小眼症的患病率估计为每10,000人0.2-3.0,80%的病例报告有非眼部受累。遗传性眼病已在狗中广泛和描述性地表征，和眼部疾病的犬模型在揭示病理生理学和开发新疗法方面发挥了重要作用。在葡萄牙水犬中发现了一种以小眼症为特征的综合征性疾病的天然犬模型。由于非眼部发现包括牙釉质畸形，发育迟缓,贫血,和血小板减少症,因此，我们将这种疾病称为犬先天性小眼伴造血缺陷。全基因组关联研究和纯合性作图在犬4号染色体上检测到2Mb候选区。针对Canfam4参考的全基因组测序和作图显示了DNAJC1基因外显子2中的短散布元件插入（g.74,274,883ins[T70]TGCTGCTTGGATT）。随后对较大的葡萄牙水犬种群进行基于实时PCR的大规模基因分型发现，纯合突变基因型与具有造血缺陷表型的犬先天性小眼完全相关。DNAJC21中的双等位基因变异主要与3型骨髓衰竭综合征相关，其表型与范可尼贫血有一定程度的重叠，先天性角化障碍,Shwachman-Diamond综合征,Diamond-Blackfan贫血,以及显示血小板减少症的个体的报告，microdontia,和小眼症。我们,因此,提出犬先天性小眼与造血缺陷作为DNAJC21相关综合征的自然发生模型。
