Rare Mutations of FGFR2 Causing Apert Syndrome: Identification of the First Partial Gene Deletion, and an Alu Element Insertion From a New Subfamily
Rare Mutations of FGFR2 Causing Apert Syndrome: Identification of the First Partial Gene Deletion, and an Alu Element Insertion From a New Subfamily
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DOI：
10.1002/humu.20825
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发表时间：
2009-02-01
期刊：
影响因子：
3.9
通讯作者：
Wilkie, Andrew O. M.
中科院分区：
文献类型：
--
作者：
Bochukova, Elena G.;Roscioli, Tony;Wilkie, Andrew O. M.
阿佩尔综合征（AS）是一种严重的疾病，其特征是颅缝早闭和手脚复杂的并指。成纤维细胞生长因子受体 2 (FGFR2) 外显子 IIIa 中的两个杂合功能获得性取代（Ser252Trp 和 Pro253Arg）导致了超过 98% 的病例。在这里，我们描述了两名患者中 FGFR2 的两种新突变，这两名患者之前在我们的 227 例 AS 病例队列中未发现突变。第一个是 1.93 kb 的删除，删除了外显子 IIIc 和侧翼内含子的大部分。这是在任何患有颅缝早闭的个体中描述的第一个大型 FGFR2 缺失。另一个突变是外显子 IIIc 中 5' 截短的 Alu 插入。这是 AS 中发现的第三个 Alu 插入；所有这些都发生在仅 104 bp 的间隔内，与背景基因组比率相比，富集了超过一百万倍。我们发现插入的 Alu 元件属于一个以前不知道可移动的小亚家族，我们将其称为 Alu Yk 13。删除和插入都可能通过类似的功能获得机制起作用，其中外显子 IIIc 的破坏导致包含选择性剪接的外显子 IIIb 的 FGFR2 剪接形式的非法间充质表达。所有与 Alu 相关的 AS 插入都出现在父系种系中；我们提出，它们在 FGFR2 中的富集是由突变精原祖细胞的正选择驱动的，这种机制类似于解释为什么经典 AS 核苷酸取代在精子中也达到异常高水平的机制。
Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases. The first is a 1.93-kb deletion, removing exon IIIc and substantial portions of the flanking introns. This is the first large FGFR2 deletion described in any individual with craniosynostosis. The other mutation is a 5' truncated Alu insertion into exon IIIc. This is the third Alu insertion identified in AS; all have occurred within an interval of only 104 bp, representing an enrichment of over a million-fold compared to the background genomic rate. We show that the inserted Alu element belongs to a small subfamily, not previously known to be mobile, which we term Alu Yk 13. Both the deletion and insertion are likely to act by a similar gain-of-function mechanism in which disruption of exon IIIc leads to illegitimate mesenchymal expression of an FGFR2 spliceform containing the alternatively spliced exon IIIb. All the AS, associated Alu insertions have arisen in the paternal germline; we propose that their enrichment in FGFR2 is driven by positive selection of the mutant spermatogonial progenitors, a mechanism analogous to that explaining why the canonical AS nucleotide substitutions also reach exceptionally high levels in sperm.