Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay.
Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay.
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DOI：
10.1002/humu.21457
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发表时间：
2011-04
期刊：
影响因子：
3.9
通讯作者：
Wilkie, Andrew O. M.
中科院分区：
文献类型：
--
作者：
Jenkins, Dagan;Baynam, Gareth;De Catte, Luc;Elcioglu, Nursel;Gabbett, Michael T.;Hudgins, Louanne;Hurst, Jane A.;Jehee, Fernanda Sarquis;Oley, Christine;Wilkie, Andrew O. M.
Carpenter综合征是一种罕见的常染色体隐性遗传疾病，其特征是颅缝早闭、多并指、肥胖和其他先天性畸形的组合，由编码小GTP酶的Rab 23家族成员的突变引起。在16个家系中，有15个是由截短突变的纯合性引起的，目前在一个复合杂合子中只发现了一个错义突变。在这里，我们描述了另外8个独立的家庭，包括10个受影响的个人与卡彭特综合征，谁是积极的突变RAB 23。我们报告了第一个纯合错义突变和框内缺失，突出了RAB 23功能的关键残基，以及第一个剪接位点突变。多缝颅缝早闭症和多并指畸形在所有的患者中均存在，并且外生殖器异常在男孩中是普遍的。高出生体重在目前的患者组中并不明显，但报告了进一步的偏侧缺陷证据。没有明显的基因型-表型相关性。我们提供的实验证据表明，编码截短突变的转录本受到无义介导的衰变，这在许多RAB 23突变的发病机制中起着重要作用。这些观察结果完善了卡彭特综合征的表型谱，并为分子发病机制提供了新的见解。© 2011 Wiley-Liss公司。
Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis. © 2011 Wiley-Liss, Inc.
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影响因子：
3.9
作者：
Johnston, Jennifer J.;Sapp, Julie C.;Turner, Joyce T.;Amor, David;Aftimos, Salim;Aleck, Kyrieckos A.;Bocian, Maureen;Bodurtha, Joann N.;Cox, Gerald F.;Curry, Cynthia J.;Day, Ruth;Donnai, Dian;Field, Michael;Fujiwara, Ikuma;Gabbett, Michael;Gal, Moran;Graham, John M., Jr.;Hedera, Peter;Hennekam, Raoul C. M.;Hersh, Joseph H.;Hopkin, Robert J.;Kayserili, Hulya;Kidd, Alexa M. J.;Kimonis, Virginia;Lin, Angela E.;Lynch, Sally Ann;Maisenbacher, Melissa;Mansour, Sahar;McGaughran, Julie;Mehta, Lakshmi;Murphy, Helen;Raygada, Margarita;Robin, Nathaniel H.;Rope, Alan F.;Rosenbaum, Kenneth N.;Schaefer, G. Bradley;Shealy, Amy;Smith, Wendy;Soller, Maria;Sommer, Annmarie;Stalker, Heather J.;Steiner, Bernhard;Stephan, Mark J.;Tilstra, David;Tomkins, Susan;Trapane, Pamela;Tsai, Anne Chun-Hui;Van Allen, Margot I.;Vasudevan, Pradeep C.;Zabel, Bernhard;Zunich, Janice;Black, Graeme C. M.;Biesecker, Leslie G.
通讯作者：
Biesecker, Leslie G.
影响因子：
2
作者：
Alessandri, Jean-Luc;Dagoneau, Nathalie;Cormier-Daire, Valerie
通讯作者：
Cormier-Daire, Valerie
影响因子：
9.8
作者：
Jenkins, Dagan;Seelow, Dominik;Wilkie, Andrew O. M.
通讯作者：
Wilkie, Andrew O. M.
影响因子：
2
作者：
Kini, Usha;Hurst, Jane A.;Wilkie, Andrew O. M.
通讯作者：
Wilkie, Andrew O. M.
影响因子：
9.8
作者：
Johnston, JJ;Olivos-Glander, I;Biesecker, LG
通讯作者：
Biesecker, LG