Gutierrez-Roelens Ilse, Sluysmans Thierry, Jorissen Mark, Amyere Mustapha, Vikkula Miikka
Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium.
Eur J Hum Genet. 2006 Jul;14(7):809-15. doi: 10.1038/sj.ejhg.5201631. Epub 2006 Apr 26.
Asymmetric positioning of internal organs is a characteristics of vertebrates. The normal left-right anatomic positioning, situs solitus, sometimes does not occur normaly, leading to laterality defects. Studies in animal models have shown that laterality decisions are mediated by a cascade of genes that lead to the asymmetric expression of Nodal, LEFTA, LEFTB and PITX2 in the lateral plate mesoderm. A search for mutations in genes implicated in left-right patterning in animal models allowed genes associated with heterotaxia defects in humans to be identified. However, these genes explain only a small percentage of human situs defects, suggesting that other genes must play a role. In this study, we report a consanguineous family of Turkish origin, composed of two unaffected parents and three children, two of whom presented Kartagener syndrome. On the basis of their family history, we hypothesize autosomal recessive mode of inheritance. A genotype analysis with polymorphic markers did not show linkage with any known genes or loci causing laterality disorders. Array CGH did not detect a duplication or microdeletion greater than 1 Mb as a possible cause. Genome wide screening using 10 K Affymetrix SNP chips was performed, allowing the identification of two regions of autozygosity, one in chromosome 1 and the other on chromosome 7. In the chromosome 1 locus, a strong candidate gene, encoding the kinesin-associated protein 3 (KIF3AP) was not mutated, based on SSCP/heteroduplex analysis and direct sequencing. These data provide a basis for the identification of a novel gene implicated in Kartagener syndrome.
内脏器官的不对称定位是脊椎动物的一个特征。正常的左右解剖定位，即 situs solitus，有时会出现异常，导致左右侧缺陷。动物模型研究表明，左右侧决定是由一系列基因介导的，这些基因导致侧板中胚层中 Nodal、LEFTA、LEFTB 和 PITX2 的不对称表达。在动物模型中寻找与左右模式相关的基因突变，使得与人类内脏反位缺陷相关的基因得以被识别。然而，这些基因仅能解释一小部分人类 situs 缺陷，这表明其他基因也必定发挥作用。在本研究中，我们报告了一个来自土耳其的近亲家庭，由两位未受影响的父母和三个孩子组成，其中两个孩子患有卡塔格内综合征。基于他们的家族病史，我们推测其遗传方式为常染色体隐性遗传。使用多态性标记进行的基因型分析未显示与任何已知的导致左右侧障碍的基因或基因座存在连锁关系。阵列比较基因组杂交未检测到大于 1 Mb 的重复或微缺失作为可能的病因。使用 10 K Affymetrix SNP 芯片进行全基因组筛选，识别出两个纯合区域，一个在 1 号染色体上，另一个在 7 号染色体上。在 1 号染色体基因座上，基于单链构象多态性/异源双链分析和直接测序，编码驱动蛋白相关蛋白 3（KIF3AP）的一个强候选基因未发生突变。这些数据为识别一个与卡塔格内综合征相关的新基因提供了基础。
