Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder
Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder
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DOI：
10.1007/s00439-014-1475-8
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发表时间：
2014-11-01
期刊：
影响因子：
5.3
通讯作者：
Vincent, John B.
中科院分区：
文献类型：
--
作者：
Ahmed, Iltaf;Mittal, Kirti;Vincent, John B.
镜像运动（MRMV）是身体一侧的不自主运动反映另一侧的自主运动。先天性镜像运动障碍是一种罕见的，典型的常染色体显性疾病，尽管有人怀疑一些散发病例可能是由于隐性遗传。利用连锁分析和候选基因方法，迄今为止有两个基因与先天性MRMV疾病有关：编码netrin受体的18q21.2 （MRMV1）上的DCC和参与维持基因组完整性的15q15.1 （MRMV2）上的RAD51。在这里，我们描述了一个有11例先天性MRMV疾病的巴基斯坦大近亲家族，跨越五代，可能是常染色体隐性遗传。DCC和RAD51的Sanger测序未发现突变。然后，我们使用微阵列基因分型和自合子作图来确定受影响个体之间的共同纯合子区域。我们在22q13.1染色体上发现了一个类似3.3 Mb的大自合区（Chr22:36605976-39904648）。我们使用Sanger测序排除了该区域内的几个候选基因，包括DMC1和NPTXR。采用全外显子组测序，发现动力蛋白轴突轻链4基因dal4剪接位点突变。这种剪接位点的改变导致DNAL4蛋白外显子3的跳变，以及28个氨基酸的缺失。使用Simwalk2进行连锁分析，该位点的最大Lod评分为6.197。dal4功能是否或如何与DCC或RAD51功能相关尚不清楚。此外，没有证据表明受影响的家庭成员中存在原发性纤毛运动障碍、反位或精子缺陷，鉴于DNAL4在轴突动力蛋白复合物中的假定作用，这可能是可以预期的。我们认为，dal4在胞质动力蛋白复合体中发挥作用，特别是在胼胝体的互交神经元中。反过来，这可能会导致错误的跨脑连接，从而导致MRMV。
Mirror movements (MRMV) are involuntary movements on one side of the body that mirror voluntary movements on the opposite side. Congenital mirror movement disorder is a rare, typically autosomal-dominant disorder, although it has been suspected that some sporadic cases may be due to recessive inheritance. Using a linkage analysis and a candidate gene approach, two genes have been implicated in congenital MRMV disorder to date: DCC on 18q21.2 (MRMV1), which encodes a netrin receptor, and RAD51 on 15q15.1 (MRMV2), which is involved in the maintenance of genomic integrity. Here, we describe a large consanguineous Pakistani family with 11 cases of congenital MRMV disorder reported across five generations, with autosomal recessive inheritance likely. Sanger sequencing of DCC and RAD51 did not identify a mutation. We then employed microarray genotyping and autozygosity mapping to identify a shared region of homozygosity-by-descent among the affected individuals. We identified a large autozygous region of similar to 3.3 Mb on chromosome 22q13.1 (Chr22:36605976-39904648). We used Sanger sequencing to exclude several candidate genes within this region, including DMC1 and NPTXR. Whole exome sequencing was employed, and identified a splice site mutation in the dynein axonemal light chain 4 gene, DNAL4. This splice site change leads to skipping of exon 3, and omission of 28 amino acids from DNAL4 protein. Linkage analysis using Simwalk2 gives a maximum Lod score of 6.197 at this locus. Whether or how DNAL4 function may relate to the function of DCC or RAD51 is not known. Also, there is no suggestion of primary ciliary dyskinesis, situs inversus, or defective sperm in affected family members, which might be anticipated given a putative role for DNAL4 in axonemal-based dynein complexes. We suggest that DNAL4 plays a role in the cytoplasmic dynein complex for netrin-1-directed retrograde transport, and in commissural neurons of the corpus callosum in particular. This, in turn, could lead to faulty cross-brain wiring, resulting in MRMV.