Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome

Giacomo Bitetto, Dario Ronchi, Sara Bonato, Alessandra Pittaro, Giacomo Monzio Compagnoni, Andreina Bordoni, Sabrina Salani, Emanuele Frattini, Gianluca Lopez, Fulvia Milena Cribiù, Stefania Corti, Giacomo P. Comi, Nereo Bresolin, Alessio Di Fonzo

Research output: Contribution to journalArticlepeer-review


Allgrove syndrome (AS) is a rare disease with broad neurological involvement. Neurodegeneration can affect spinal motor neurons, Purkinje cells, striatal neurons and the autonomic system. The mechanisms that lead to neuronal loss are still unclear. Recessive mutations in the AAAS gene affect the encoded protein Aladin, which would normally localize to the cytoplasmic face of the nuclear membrane as part of the nuclear pore complex (NPC). While the NPC is known to be a key factor for nucleocytoplasmic transport, the precise role of Aladin has not been elucidated yet. Here, we explored the consequences of the homozygous AAAS mutation c.464G>A (p.R155H) in central nervous system tissues and fibroblasts of a novel AS patient presenting motor neuron disease, cerebellar ataxia and autonomic dysfunction. Neuropathological analyses showed severe loss of motor neurons and Purkinje cells, with significant reduction in the perinuclear expression of Aladin. A reduced amount of protein was detected in the nuclear membrane fraction of the patient's brain. RNA analysis revealed a significant reduction of the transcript AAAS-1, while the AAAS-2 transcript was upregulated in fibroblasts. To our knowledge, this is the first study to demonstrate the effects of AAAS mutations in the human central nervous system.

Original languageEnglish
Pages (from-to)3921-3927
Number of pages7
JournalHuman Molecular Genetics
Issue number23
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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