Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber Syndrome
Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber Syndrome
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DOI：
10.1002/humu.9496
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发表时间：
2007-06-01
期刊：
影响因子：
3.9
通讯作者：
Bergman, Carsten
中科院分区：
文献类型：
--
作者：
Frank, Valeska;Bruechle, Nadina Ortiz;Bergman, Carsten
梅克尔-格鲁伯综合征（MKS）是一种常染色体隐性遗传病，通常是致死性的多系统疾病，以中枢神经系统早期发育异常、囊性肾发育不良、肝胆管板畸形和轴后多指畸形为特征。三个MKS位点已经被定位，最近，两个基因被鉴定出来：MKS1在高加索家族的17q22上，MKS3在阿曼和巴基斯坦家族的8q22上，把MKS放在了不断增长的纤毛疾病（“纤毛病”）的名单上。我们对14个不同种族血统的近亲和/或多重家族的MKS1-3进行了连锁分析，这些家族的组织学诊断和每个家族中至少有三种典型的MKS表现。出乎意料的是，只有5个家族与任何已知的MKS位点相关，这清楚地表明了位点的进一步异质性。所有5个家族都显示出MKS1的纯合性，有趣的是，它们都是非高加索血统。MKS1测序显示其中两个家系没有突变，而在其他三个家庭和另外一个散发性德国患者中发现了不同的新型剪接缺陷。考虑到我们所有的突变和已知的4个MKS1突变中的2个导致了异常剪接（而另外两个已知的突变是移码突变），我们假设剪接缺陷是MKS1的一个关键突变机制，MKS1显然是MKS的主要基因座之一和关键参与者。我们的研究结果表明，MKS1突变并不局限于高加索人的基因库，并提示MKS进一步的遗传异质性。总的来说，我们的数据对MKS的遗传咨询和测试方法有直接的影响。(c) 2007 Wiley-Liss, Inc。
Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS. (c) 2007 Wiley-Liss, Inc.