Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.
Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.
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DOI：
10.1136/jmedgenet-2016-104436
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发表时间：
2017-06
影响因子：
4
通讯作者：
Thauvin-Robinet C
中科院分区：
文献类型：
--
作者：
Bruel AL;Franco B;Duffourd Y;Thevenon J;Jego L;Lopez E;Deleuze JF;Doummar D;Giles RH;Johnson CA;Huynen MA;Chevrier V;Burglen L;Morleo M;Desguerres I;Pierquin G;Doray B;Gilbert-Dussardier B;Reversade B;Steichen-Gersdorf E;Baumann C;Panigrahi I;Fargeot-Espaliat A;Dieux A;David A;Goldenberg A;Bongers E;Gaillard D;Argente J;Aral B;Gigot N;St-Onge J;Birnbaum D;Phadke SR;Cormier-Daire V;Eguether T;Pazour GJ;Herranz-Pérez V;Goldstein JS;Pasquier L;Loget P;Saunier S;Mégarbané A;Rosnet O;Leroux MR;Wallingford JB;Blacque OE;Nachury MV;Attie-Bitach T;Rivière JB;Faivre L;Thauvin-Robinet C
口面指综合征（OFDS）收集罕见的遗传性疾病，其特征是面部，口腔和手指异常，并伴有广泛的其他特征（多囊肾病，脑畸形等），以描绘不断增长的OFD亚型列表。最常见的OFD I型是由编码中心体蛋白的OFD 1基因的杂合突变引起的。OFDS广泛的临床异质性表明其他纤毛基因的参与。15年来，我们一直致力于确定OFDS的分子基础。最近发展的全外显子组测序（WES）极大地帮助了这一努力。在这里，我们提出了我们所有的已发表和未发表的结果WES在24 OFDS的情况下。我们确定了5个新基因（C2CD 3，TMEM 107，INTU，KIAA 0753，IFFT 57）的致病变异，并将其他纤毛病中4个基因（C5 orf 42，TMEM 138，TMEM 231，WDPCP）的临床谱与OFDS相关。在先前与OFDS有关的两个基因中也检测到突变。功能研究揭示了OFDS中中心粒伸长、过渡区和鞭毛内运输缺陷的参与，从而表征了三种纤毛蛋白模块：复合物KIAA 0753-FOPNL-OFD 1，中心粒伸长的调节剂; MKS模块，过渡区的主要组成部分;和IFT-A组装所必需的CPLANE复合物。OFDS现在似乎是一个独特的亚组纤毛病变具有广泛的异质性，这使得最初的分类过时。可以提出仅限于三种常见/明确描述的亚型的临床分类，对于不符合这三种主要亚型之一的患者，可以基于基因型进行进一步分类。
Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterized by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFD subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 OFDS cases. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231, WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterizing three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the MKS module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these 3 main subtypes, a further classification could be based on the genotype.
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影响因子：
3.5
作者：
Poretti, A.;Brehmer, U.;Boltshauser, E.
通讯作者：
Boltshauser, E.
影响因子：
9.8
作者：
Li C;Jensen VL;Park K;Kennedy J;Garcia-Gonzalo FR;Romani M;De Mori R;Bruel AL;Gaillard D;Doray B;Lopez E;Rivière JB;Faivre L;Thauvin-Robinet C;Reiter JF;Blacque OE;Valente EM;Leroux MR
通讯作者：
Leroux MR
影响因子：
3.3
作者：
Giorgio, Giovanna;Alfieri, Mariaevelina;Franco, Brunella
通讯作者：
Franco, Brunella
影响因子：
2
作者：
Gurrieri, Fiorella;Franco, Brunella;Neri, Giovanni
通讯作者：
Neri, Giovanni
影响因子：
3.5
作者：
Chevrier, Veronique;Bruel, Ange-Line;Thauvin-Robinet, Christel
通讯作者：
Thauvin-Robinet, Christel