CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant
CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant
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DOI：
10.1136/jmg.2010.080226
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Furuichi, Tatsuya;Dai, Jin;Ikegawa, Shiro
背景Desbuquois发育不良（DD）是一种以身材矮小、全身性骨骼发育不良和骨成熟提前为特征的遗传性疾病。DD在临床上和影像学上都是异质性的，并且根据副掌骨的存在（1型）或缺失（2型）区分了两种亚型。此外，一个明显不同的变种没有额外的掌骨，但短掌骨和长指骨（金变种）最近已被描述。编码CANT 1的基因突变在DD 1型患者的一个亚组中发现了一种钙激活核苷酸酶1（calciumactivatednucleotidase 1）。（一个1型，两个2型，通过对所有编码外显子及其侧翼内含子进行直接测序，检查了5个Kim变体）的CANT 1突变。结果在7个家族中发现了8个不同的突变（1个1型，1个2型和所有5个Kim变体）：3个是无意义的，5个是错义的。所有错义突变均发生在CANT 1核苷酸酶保守区的高度保守氨基酸上。体外核苷酸酶活性测定结果表明，CANT 1错义突变均与功能丧失有关。结论CANT 1突变产生的临床-放射学谱必须扩展到包括DD 2型和Kim变异。虽然存在或不存在额外的掌骨骨化中心已被用来区分亚型的DD，这个迹象是不是一个独特的标准来预测DD的分子基础。
Background Desbuquois dysplasia (DD) is a recessively inherited condition characterised by short stature, generalised skeletal dysplasia and advanced bone maturation. DD is both clinically and radiographically heterogeneous, and two subtypes have been distinguished based on the presence (type 1) or absence (type 2) of an accessory metacarpal bone. In addition, an apparently distinct variant without additional metacarpal bone but with short metacarpals and long phalanges (Kim variant) has been described recently. Mutations in the gene that encodes for CANT1 (calcium-activated nucleotidase 1) have been identified in a subset of patients with DD type 1.Methods A series of 11 subjects with DD from eight families (one type 1, two type 2, five Kim variant) were examined for CANT1 mutations by direct sequencing of all coding exons and their flanking introns.Results Eight distinct mutations were identified in seven families (one type 1, one type 2 and all 5 Kim variant): three were nonsense and five were missense. All missense mutations occurred at highly conserved amino acids in the nucleotidase conserved regions of CANT1. Measurement of nucleotidase activity in vitro showed that the missense mutations were all associated with loss-of-function.Conclusion The clinical-radiographic spectrum produced by CANT1 mutations must be extended to include DD type 2 and Kim variant. While presence or absence of an additional metacarpal ossification centre has been used to distinguish subtypes of DD, this sign is not a distinctive criterion to predict the molecular basis in DD.