Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, People's Republic of China.
National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou, 450014, People's Republic of China.
Orphanet J Rare Dis. 2020 Sep 9;15(1):240. doi: 10.1186/s13023-020-01492-8.
Desbuquois dysplasia (DBQD) was a rare autosomal recessive skeletal dysplasia. Calcium activated nucleotidase 1 (CANT1) mutation was identified as a common pathogenic change for DBQD type 1 and Kim variant but not for DBQD type 2. To our knowledge, all patients with DBQD type 1 currently found could be explained by mutations in the CANT1 gene, but mutations in the CANT1 gene might not be directly diagnosed as DBQD type 1.
We have identified two novel CANT1 mutations (mut1: c.594G > A [p.Trp198*], mut2: c.734C > T [p.Pro245Leu]) in three children from a family of Chinese origin for the first time. Two of the three children could be diagnosed as typical DBQD type 1 and one child could not be diagnosed as DBQD type 1 based on the clinical data we had. To further clarify the effect of the two mutations of the CANT1 gene, we studied the CANT1 gene expression and detected the protein secretion and nucleotide enzyme activity through cDNA cloning and expression vectors construction for wild and mutant types. The mut1 was a nonsense mutation which could lead to premature termination and produced the truncated bodies; The CANT1 dimer of mut2 was significantly reduced and even undetectable. The extracellular secretion of mut1 was extremely high while mut2 was significantly reduced compared with the wild type. And mut1 and mut2 also could result in a significant reduction in the activity of CANT1 nucleotidease. From the results we could deduce that the two mutations of the CANT1 gene were the causes of the two cases in this study.
Regarding the particularity of the cases reported in this study, the pathogenesis of CANT1 might be more complicated. The genetic and phenotype of three children with the same genetic background need to be further studied. Larger cohort of patients was needed to establish genotype-phenotype correlations in DBQD.
Desbuquois 发育不良（DBQD）是一种罕见的常染色体隐性骨骼发育不良。钙激活核苷酸酶 1（CANT1）突变被确定为 DBQD 1 型和 Kim 变异型的常见致病变化，但不是 DBQD 2 型的致病变化。据我们所知，目前发现的所有 DBQD 1 型患者都可以用 CANT1 基因突变来解释，但 CANT1 基因突变可能不能直接诊断为 DBQD 1 型。
我们首次在一个华裔家庭的 3 名儿童中发现了 2 种新的 CANT1 突变（mut1：c.594G > A [p.Trp198*]，mut2：c.734C > T [p.Pro245Leu]）。这 3 名儿童中的 2 名可被诊断为典型的 DBQD 1 型，而根据我们所掌握的临床资料，1 名儿童不能被诊断为 DBQD 1 型。为了进一步阐明 CANT1 基因突变的影响，我们通过 cDNA 克隆和表达载体构建研究了 CANT1 基因的表达，并检测了突变型和野生型 CANT1 蛋白的分泌和核苷酸酶活性。mut1 是一种无义突变，可导致提前终止并产生截短体；mut2 的 CANT1 二聚体显著减少，甚至无法检测到。与野生型相比，mut1 的细胞外分泌极高，而 mut2 则显著减少。mut1 和 mut2 还可导致 CANT1 核苷酸酶活性显著降低。从结果可以推断，CANT1 基因的这两种突变是本研究中两个病例的原因。
鉴于本研究报道的病例的特殊性，CANT1 的发病机制可能更为复杂。需要进一步研究具有相同遗传背景的 3 名儿童的遗传和表型。需要更大的患者队列来建立 DBQD 的基因型-表型相关性。
