Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1.
Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1.
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DOI：
10.1186/1471-2156-8-26
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发表时间：
2007-05-18
期刊：
影响因子：
2.9
通讯作者：
Engle EC
中科院分区：
文献类型：
--
作者：
Chan WM;Andrews C;Dragan L;Fredrick D;Armstrong L;Lyons C;Geraghty MT;Hunter DG;Yazdani A;Traboulsi EI;Pott JW;Gutowski NJ;Ellard S;Young E;Hanisch F;Koc F;Schnall B;Engle EC
先天性眼外肌纤维化 1 型和 3 型 (CFEOM1/CFEOM3) 是常染色体显性斜视疾病，似乎是由眼核和神经发育不良引起的。我们之前报道过，大多数患有 CFEOM1 的个体和极少数患有 CFEOM3 的个体都存在 KIF21A 杂合突变。 KIF21A 编码参与顺行轴突运输的驱动蛋白运动，迄今为止报道的家族性和从头突变可预测地改变仅有的几个 KIF21A 氨基酸之一——三个位于茎的第三卷曲螺旋区域，一个位于远端运动域，表明它们导致 KIF21A 功能改变。为了进一步定义 CFEOM 中 KIF21A 突变谱，我们现在已经鉴定了新加入我们研究的所有 CFEOM 先证者，并确定他们是否携带 KIF21A 突变。研究了 16 名 CFEOM1 和 29 名 CFEOM3 先证者。在三个 CFEOM1 先证者中鉴定出三个先前未报告的从头 KIF21A 突变，所有突变均位于茎的同一卷曲螺旋区域，该区域包含除先前报告的突变之一之外的所有突变。另外八名 CFEOM1 先证者携带先前在 KIF21A 中报道的三种突变；七人具有两种最常见的突变之一，而其中一人则在远端运动域中存在突变。在 5 名 CFEOM1 或任何 CFEOM3 先证者中未检测到突变。对 16 个 CFEOM1 先证者的分析揭示了 3 个新的 KIF21A 突变，并确认了 3 个报告的突变，使 CFEOM1 中报告的 KIF21A 突变总数达到 70 个突变阳性先证者中的 11 个突变。所有三个新突变都改变了 KIF21A 茎第三卷曲螺旋区域内七肽重复序列中的氨基酸，进一步凸显了该结构域的改变在 CFEOM1 病因学中的重要性。
Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A. Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands. Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.
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