Koehler Katrin, Brockmann Knut, Krumbholz Manuela, Kind Barbara, Bönnemann Carsten, Gärtner Jutta, Huebner Angela
Children's Hospital, Technical University Dresden, Dresden, Germany.
Eur J Hum Genet. 2008 Dec;16(12):1499-506. doi: 10.1038/ejhg.2008.132. Epub 2008 Jul 16.
The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G>A mutation in exon 2 that had been reported previously, and a novel c.1288C>T mutation in exon 14. At the transcriptional level, the c.251G>A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C>T, (p.Leu430Phe, L430F) mutation in a hemizygous form. With transfection experiments, we demonstrate that GFP-ALADIN(L430F) correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.
三 A 综合征由 AAAS 基因的常染色体隐性遗传突变引起，其特征为贲门失弛缓症、无泪症和肾上腺功能不全以及进行性神经功能损害。我们报告了一名 14 岁女孩，患有缓慢进展的轴索性运动神经病，小鱼际肌和小腿明显肌肉萎缩以及无泪症。AAAS 基因的突变分析显示为复合杂合突变：外显子 2 中的 c.251G>A 突变（此前已有报道）以及外显子 14 中的新突变 c.1288C>T。在转录水平上，c.251G>A 转换导致该 RNA 链异常剪接和降解，因此特定的临床症状是由半合子形式的新 c.1288C>T（p.Leu430Phe，L430F）突变引起的。通过转染实验，我们证明 GFP-ALADIN（L430F）正确定位于核孔复合体。因此，我们得出结论，该点突变损害了核孔处的 ALADIN 功能。
