Frank Valeska, Ortiz Brüchle Nadina, Mager Silke, Frints Susanna G M, Bohring Axel, du Bois Gabriele, Debatin Irmgard, Seidel Heide, Senderek Jan, Besbas Nesrin, Todt Unda, Kubisch Christian, Grimm Tiemo, Teksen Fulya, Balci Sevim, Zerres Klaus, Bergmann Carsten
Department of Human Genetics, RWTH Aachen University, Aachen, Germany.
Hum Mutat. 2007 Jun;28(6):638-9. doi: 10.1002/humu.9496.
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.
梅克尔-格鲁伯综合征（MKS）是一种常染色体隐性遗传、通常致命的多系统疾病，其特征为中枢神经系统早期发育异常、多囊性肾发育不良、肝胆管板畸形和轴后多指畸形。已定位了三个MKS基因座，最近又鉴定出两个基因：在白种人家族中位于17q22的MKS1以及在阿曼和巴基斯坦家族中位于8q22的MKS3，这使得MKS被列入不断增加的纤毛病（“纤毛相关疾病”）名单中。我们对14个不同种族起源的近亲及/或多人患病家族进行了MKS1 - 3的连锁分析，这些家族均有组织学诊断且每个家族至少有三种典型的MKS表现。出乎意料的是，只有五个家族与任何已知的MKS基因座连锁，这清楚地表明存在进一步的基因座异质性。所有这五个家族均显示MKS1纯合，有趣的是，它们均非白种人起源。对其中两个家系进行的MKS1测序未发现突变，而在另外三个家族以及一名散发的德国患者中鉴定出了不同的新型剪接缺陷。鉴于我们所有的突变以及总共四个已知的MKS1变化中有两个会导致异常剪接（而另外两个已知突变是移码突变），我们推测剪接缺陷是MKS1中的一种关键突变机制，MKS1显然是MKS的主要基因座和关键因素之一。我们的结果表明，MKS1突变并不局限于白种人基因库，并提示MKS存在进一步的遗传异质性。总体而言，我们的数据对MKS的遗传咨询和检测方法具有直接影响。
