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首页> 外文期刊>Mutagenesis >Characterisation of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient
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Characterisation of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient

机译：表征的新的RUNX2突变与丙氨酸扩大日本小脑颅骨发育不良患者

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Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypopalstic and/or aplastic clavicles, midface hypoplasia, absent or delayed closure of cranial sutures, moderately short stature, delayed eruption of permanent dentition and supernumerary teeth. The molecular pathogenesis can be explained in about two-thirds of CCD patients by haploinsufficiency of the RUNX2 gene. In our current study, we identified a novel and rare variant of the RUNX2 gene (c.181_189dupGCGGCGGCT) in a Japanese patient with phenotypic features of CCD. The insertion led an alanine tripeptide expansion (+3Ala) in the polyalanine tract. To date, a RUNX2 variant with alanine decapeptide expansion (+10Ala) is the only example of a causative variant of RUNX2 with polyalanine tract expansion to be reported, whilst RUNX2 (+1Ala) has been isolated from the healthy population. Thus, precise analyses of the RUNX2 (+3Ala) variant were needed to clarify whether the tripeptide expanded RUNX2 is a second disease-causing mutant with alanine tract expansion. We therefore investigated the biochemical properties of the mutant RUNX2 (+3Ala), which contains 20 alanine residues in the polyalanine tract. When transfected in COS7 cells, RUNX2 (+3Ala) formed intracellular ubiquitinated aggregates after 24 h, and exerted a dominant negative effect in vitro. At 24 h after gene transfection, whereas slight reduction was observed in RUNX2 (+10Ala), all of these mutants significantly activated osteoblast-specific element-2, a cis-acting sequence in the promoter of the RUNX2 target gene osteocalcin. The aggregation growth of RUNX2 (+3Ala) was clearly lower and slower than that of RUNX2 (+10Ala). Furthermore, we investigated several other RUNX2 variants with various alanine tract lengths, and found that the threshold for aggregation may be RUNX2 (+3Ala). We conclude that RUNX2 (+3Ala) is the cause of CCD in our current case, and that the accumulation of intracellular aggregates in vitro is related to the length of the alanine tract.
机译：颅骨发育不良（CCD; MIM 119600）是常染色体显性骨骼发育不良，其特征是锁骨发育不全和/或再生障碍性锁骨，中面部发育不全，颅骨缝线缺失或延迟闭合，中等身材矮小，永久性牙列萌发和牙齿数量过多。大约三分之二的CCD患者可以通过RUNX2基因的单倍不足来解释其分子发病机理。在我们当前的研究中，我们在一名具有CCD表型特征的日本患者中鉴定了RUNX2基因的一种新型且罕见的变体（c.181_189dupGCGGCGGCT）。该插入导致聚丙氨酸束中的丙氨酸三肽扩增（+ 3Ala）。迄今为止，报道了具有丙氨酸十肽扩展（+ 10Ala）的RUNX2变体是具有聚丙氨酸束扩展的RUNX2的致病性变体的唯一实例，而已从健康人群中分离出RUNX2（+ 1Ala）。因此，需要对RUNX2（+ 3Ala）变体进行精确分析，以阐明三肽扩增的RUNX2是否是第二个引起丙氨酸束扩张的致病突变体。因此，我们研究了突变体RUNX2（+ 3Ala）的生化特性，该突变体在聚丙氨酸束中包含20个丙氨酸残基。当在COS7细胞中转染时，RUNX2（+ 3Ala）在24小时后形成细胞内泛素化聚集体，并在体外发挥显性负作用。基因转染后24小时，虽然在RUNX2（+ 10Ala）中观察到轻微减少，但所有这些突变体均显着激活成骨细胞特异性element-2，即RUNX2目标基因骨钙素启动子中的顺式作用序列。 RUNX2（+ 3Ala）的聚集增长明显低于RUNX2（+ 10Ala）的聚集和缓慢。此外，我们研究了具有不同丙氨酸长度的其他几种RUNX2变体，发现聚合的阈值可能是RUNX2（+ 3Ala）。我们得出结论，在我们当前的病例中，RUNX2（+ 3Ala）是CCD的原因，并且体外细胞内聚集体的积累与丙氨酸束的长度有关。

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