Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type
Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type
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DOI：
10.1016/j.ajhg.2015.10.014
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发表时间：
2015-12-01
影响因子：
9.8
通讯作者：
Van Esch, Hilde
中科院分区：
文献类型：
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作者：
Isrie, Mala;Breuss, Martin;Van Esch, Hilde
昆泽型环状皮肤皱纹(CSC-KT)是一种遗传原因不明的特殊先天性疾病。这种疾病的表型包括特征性的环状皮肤皱纹，并伴有智力残疾、腭裂、身材矮小和畸形特征。在这里，我们报告了MAPRE2或Tubb的突变是这种综合征的遗传起源的基础。MAPRE2编码微管末端结合蛋白家族的成员之一，该家族在生长的微管+末端与鸟苷三磷酸帽结合，Tubb编码一种b-微管蛋白亚型，在发育中的大脑中大量表达。对Tubb突变体的功能分析表明，依赖于伴侣的微管蛋白异源二聚体的折叠和组装途径存在多个缺陷，导致天然异源二聚体的产量下降。Tubb突变对微管动力学也有影响。对于MAPRE2，我们发现突变导致MAPRE2与微管的结合增强，这意味着微管+末端的停留时间增加。此外，对斑马鱼头面部发育模型中MAPRE2突变的活体分析表明，这些变异最有可能通过过度活动(在隐性范式下)或通过单倍体不足(显性从头范式)扰乱鳃弓的模式。综上所述，我们的数据将CSC-KT添加到不断增长的小管蛋白病变列表中，并强调了多重遗传范例如何影响剂量敏感的生物系统，从而导致相同的临床缺陷。
Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a b-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.