Phenotypic and molecular insights into CASK-related disorders in males.
Phenotypic and molecular insights into CASK-related disorders in males.
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DOI：
10.1186/s13023-015-0256-3
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发表时间：
2015-04-12
影响因子：
3.7
通讯作者：
Kutsche K
中科院分区：
文献类型：
--
作者：
Moog U;Bierhals T;Brand K;Bautsch J;Biskup S;Brune T;Denecke J;de Die-Smulders CE;Evers C;Hempel M;Henneke M;Yntema H;Menten B;Pietz J;Pfundt R;Schmidtke J;Steinemann D;Stumpel CT;Van Maldergem L;Kutsche K
x连锁CASK基因的杂合子功能缺失突变导致女性进行性小头畸形伴脑桥和小脑发育不全（MICPCH）和严重智力残疾（ID）。在男性中也报道了不同的CASK突变。相关的表型范围从非综合征性ID到伴有小脑发育不全的大田原综合征。然而，迄今为止，男性的表型谱尚未得到系统的评估。我们通过靶向Sanger测序、拷贝数分析（MLPA和/或FISH）和阵列CGH在8例新的无亲缘关系男性患者中发现了CASK改变。用RT-PCR分析CASK转录本，并进行测序。免疫印迹法用于检测患者源性细胞中的CASK蛋白。我们回顾了之前报道的8例患者和28例cask突变阳性男性的临床表型和自然史，并与现有的分子数据进行了关联。CASK的改变包括1个无义突变、1个5-bp缺失、1个起始密码子突变和5个部分基因缺失和重复；其中7个是新生的，包括3个体细胞嵌合，1个是家族性的。在三个受试者中，特定的mRNA连接片段表明CASK外显子的串联重复破坏了基因的完整性。5-bp的缺失导致了多个异常的CASK mrna。在CASK功能丧失突变患者的成纤维细胞中，未检测到CASK蛋白。患有严重CASK突变或携带半胚突变的个体仍然显示出可检测的蛋白质量。根据先前报道的8例新患者和所有cask突变阳性男性，可以区分出代表临床连续体的三个表型组：(i)由半合子功能丧失突变引起的MICPCH伴有严重癫痫性脑病，（ii） MICPCH与马赛克状态失活改变或部分浸润性突变相关，以及（iii）由CASK错义和剪接突变引起的综合征/非综合征性轻度至重度ID伴或不伴眼球震颤，这些突变使CASK蛋白保持完整，但可能改变其功能或减少正常蛋白的数量。我们的研究结果有助于对CASK基因进行集中测试，并解释由下一代测序确定的与三组表型相似的病例中的序列变异。本文的在线版本（doi:10.1186/s13023-015-0256-3）包含补充材料，仅供授权用户使用。
Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups. The online version of this article (doi:10.1186/s13023-015-0256-3) contains supplementary material, which is available to authorized users.
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影响因子：
4
作者：
Moog, Ute;Kutsche, Kerstin;Uyanik, Goekhan
通讯作者：
Uyanik, Goekhan
影响因子：
2
作者：
Takanashi, Jun-ichi;Okamoto, Nobuhiko;Inazawa, Johji
通讯作者：
Inazawa, Johji
影响因子：
5.3
作者：
Piluso, G;Carella, M;Nigro, V
通讯作者：
Nigro, V
影响因子：
3.7
作者：
Burglen L;Chantot-Bastaraud S;Garel C;Milh M;Touraine R;Zanni G;Petit F;Afenjar A;Goizet C;Barresi S;Coussement A;Ioos C;Lazaro L;Joriot S;Desguerre I;Lacombe D;des Portes V;Bertini E;Siffroi JP;de Villemeur TB;Rodriguez D
通讯作者：
Rodriguez D
DOI：
10.1002/ajmg.c.31403
发表时间：
2014-06-01
影响因子：
3.1
作者：
Rudnik-Schoeneborn, Sabine;Barth, Peter G.;Zerres, Klaus
通讯作者：
Zerres, Klaus