title: Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation.
abstract: 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.
authors.affiliation: Children's Hospital, Technical University Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krumbholz
authors.forename: K
authors.initials: K
authors.lastname: Koehler
authors.forename: A
authors.initials: A
authors.lastname: Huebner
mesh_terms: D000224:Addison Disease / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004931:Esophageal Achalasia / Q000235:genetics; D016368:Frameshift Mutation; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D012326:RNA Splicing / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013577:Syndrome; D014162:Transfection; D014985:Xerophthalmia / Q000235:genetics
chemical_list: C416506:AAAS protein, human; D018389:Codon, Nonsense; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D011994:Recombinant Proteins; D004247:DNA