Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.
Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.
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CEP120和CC2D2A中遗传变异的更新，重点是基因型 - 表型相关性，组织特定的转录本和探索突变特异性外显子跳过疗法。
DOI：
10.1002/mgg3.1603
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发表时间：
2021-12
影响因子：
2
通讯作者：
Sayer JA
中科院分区：
文献类型：
--
作者：
Barroso-Gil M;Olinger E;Ramsbottom SA;Molinari E;Miles CG;Sayer JA
纤毛基因的突变导致一系列重叠和不同的临床症状(纤毛疾病)。CEP120和CC2D2A是这种遗传异质性和多效性的典型例子，因为这两个基因的突变都会导致Joubert综合征，但也分别与骨骼纤毛疾病和Meckel综合征相关。这种表型变异的分子基础尚不清楚，但基本外显子跳过可能通过组织特异性地保存表达的功能蛋白的量而有助于耐受有害突变。我们系统地回顾和注释了CEP120和CC2D2A相关疾病中报告的遗传变异和临床表现，并结合计算机和体外方法研究组织特异性转录本，并确定外显子跳过的分子靶点。我们证实了与截断CC2D2A突变相关的更严重的临床表现。我们确定并证实了肾脏中的基本外显子跳跃，这可能与器官特异性疾病的表现有关。最后，我们提出了一种多通道方法来分类符合外显子跳跃的外显子。通过绘制已报道的变异图谱，7个CC2D2A外显子的14个截断突变被确定为有可能通过靶向外显子跳过来挽救，这种方法已经在临床上用于其他人类遗传性疾病。CC2D2A的基因型-表型相关性支持零等位基因的危害性，而CC2D2A而不是CEP120提供了治疗外显子跳过方法的可能性。CEP120和CC2D2A的突变导致Joubert综合征，但也分别与骨骼纤毛疾病和Meckel综合征相关。在这里，我们注释了CEP120和CC2D2A相关疾病中描述的遗传变异，并确认了双等位基因截断CC2D2A突变的更严重的临床表现。结合计算机和体外研究，我们确定了肾脏中替代的基础外显子跳跃，可能与器官特定的疾病表现相关，并提出了一种多模式方法来分类服从外显子跳跃的外显子。
Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue‐specific preservation of the amount of expressed functional protein. We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120‐ and CC2D2A‐associated disease and we combined in silico and ex vivo approaches to study tissue‐specific transcripts and identify molecular targets for exon skipping. We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Genotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches. Mutations in CEP120 and CC2D2A cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. Here we annotate genetic variants described in CEP120‐ and CC2D2A‐associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations and propose a multimodal approach to classify exons amenable to exon skipping.
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影响因子：
4.5
作者：
Bachmann-Gagescu R;Dona M;Hetterschijt L;Tonnaer E;Peters T;de Vrieze E;Mans DA;van Beersum SE;Phelps IG;Arts HH;Keunen JE;Ueffing M;Roepman R;Boldt K;Doherty D;Moens CB;Neuhauss SC;Kremer H;van Wijk E
通讯作者：
van Wijk E
影响因子：
2.6
作者：
Hartill V;Szymanska K;Sharif SM;Wheway G;Johnson CA
通讯作者：
Johnson CA
影响因子：
4
作者：
Al-Hamed MH;Kurdi W;Alsahan N;Alabdullah Z;Abudraz R;Tulbah M;Alnemer M;Khan R;Al-Jurayb H;Alahmed A;Tahir AI;Khalil D;Edwards N;Al Abdulaziz B;Binhumaid FS;Majid S;Faquih T;El-Kalioby M;Abouelhoda M;Altassan N;Monies D;Meyer B;Sayer JA;Albaqumi M
通讯作者：
Albaqumi M
影响因子：
7.2
作者：
Braun DA;Hildebrandt F
通讯作者：
Hildebrandt F
影响因子：
9.8
作者：
Gorden, Nicholas T.;Arts, Heleen H.;Doherty, Dan
通讯作者：
Doherty, Dan