Krumbholz M, Koehler K, Huebner A
Children's Hospital, Technical University Dresden, Germany.
Biochem Cell Biol. 2006 Apr;84(2):243-9. doi: 10.1139/o05-198.
The triple A syndrome is a complex and multisystemic autosomal recessive disease with the 3 main symptoms of adrenal insufficiency, alacrima, and achalasia accompanied by neurological impairment. Mutations in the AAAS gene on chromosome 12q13 are responsible for the disorder. AAAS encodes a protein named ALADIN, which belongs to the family of WD-repeat-containing proteins and has been shown to localize to nuclear pore complexes. The function of the protein is not clear. It is supposed that ALADIN plays an important role in RNA and (or) protein trafficking between the nucleus and cytoplasm. With transfection experiments, we analyzed the cellular localization of the wild-type and 17 natural mutant variants (9 missense, 5 nonsense, 3 frameshift mutations) of ALADIN. We show that most mutations cause mislocalization of the mutant ALADIN proteins in the cytoplasm. In contrast, some variants with mutations located at the N-terminus (Q15K, L25P) and 3 artificial C-terminus mutations (Q490X, R493X, and V497X) remain at the nuclear pore. Using a patient cell line, we show that the mutation 43C>A in exon 1 does not cause a missense mutation Q15K but, rather, results in aberrant splicing.
三 A 综合征是一种复杂的多系统常染色体隐性疾病，主要症状为肾上腺功能不全、无泪症和贲门失弛缓症，并伴有神经功能障碍。12q13 染色体上的 AAAS 基因突变是导致该疾病的原因。AAAS 编码一种名为 ALADIN 的蛋白质，该蛋白质属于含 WD 重复序列的蛋白质家族，已被证明定位于核孔复合体。该蛋白质的功能尚不清楚。推测 ALADIN 在细胞核与细胞质之间的 RNA 和（或）蛋白质运输中起重要作用。通过转染实验，我们分析了 ALADIN 的野生型和 17 种天然突变变体（9 种错义突变、5 种无义突变、3 种移码突变）的细胞定位。我们发现大多数突变会导致突变的 ALADIN 蛋白在细胞质中定位错误。相比之下，一些位于 N 端的突变变体（Q15K、L25P）和 3 种人工 C 端突变（Q490X、R493X 和 V497X）仍保留在核孔处。使用患者细胞系，我们发现外显子 1 中的 43C>A 突变不会导致错义突变 Q15K，而是导致异常剪接。
