Disruption of RAB40AL function leads to Martin-Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder
Disruption of RAB40AL function leads to Martin-Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder
复制标题
DOI：
10.1136/jmedgenet-2011-100575
复制
发表时间：
2012-05-01
影响因子：
4
通讯作者：
Martin, Donna M.
中科院分区：
文献类型：
--
作者：
Bedoyan, Jirair Krikor;Schaibley, Valerie M.;Martin, Donna M.
背景和目的Martin-Probst综合征（MPS）是一种罕见的X连锁疾病，其特征是耳聋、认知障碍、身材矮小和明显的颅面畸形等。方法和结果在两名患有MPS的受影响的相关男性受试者中进行大规模平行测序，鉴定出RAB 40 AL（也称为RLGP）错义突变（chrX：102，079，078 -102，079，079 AC-> GA p.D59G; hg 18）。RAB 40 AL编码一个小的Ras样GT3蛋白，具有一个细胞因子信号传导盒抑制因子。p.D59G变体位于β-2和β-3链之间的GTdR结构域的高度保守区域。作者利用RT-PCR表明，RAB 40 AL在人胎儿和成人的大脑和肾脏以及成人的肺、心脏、肝脏和骨骼肌中表达。RAB 40 AL似乎是灵长类动物的创新，在小鼠、非洲爪蟾或斑马鱼中没有发现直系同源物。Western分析和荧光显微镜的GFP标记的RAB 40 AL结构从瞬时转染的COS 7细胞显示，D59 G错义的变化，使RAB 40 AL不稳定，破坏其胞质localisation.Conclusions这是第一次研究表明，突变的RAB 40 AL与人类疾病。将RAB 40 AL鉴定为MPS中突变的基因允许进一步研究RAB 40 AL的分子机制及其在诸如认知、听力和骨骼发育等多种过程中的作用。
Background and aim Martin-Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS.Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC -> GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p. D59G variant is located in a highly conserved region of the GTPase domain between beta-2 and beta-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation.Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development.