The triple A syndrome (MIM#231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima, and a variety of neurological and dermatological features. The triple A syndrome is caused by mutations in the AAAS gene, which encodes a protein known as ALADIN (ALacrima Achalasia aDrenal Insufficiency Neurologic disorder). ALADIN is a new WD-repeat protein that has no significant homology to any previously identified WD-repeat protein. It has been shown that it colocalizes with nuclear pore complexes (NPCs), a finding that strongly suggests an involvement of ALADIN in nucleocytoplasmic transport. An investigation of 110 families with triple A syndrome disclosed mutation hot spots including Q15K (exon 1), and S293P (exon 8), which occur in 17 and 21 families from different geographical regions, respectively. The variable phenotype of all patients cannot be correlated with the localization and the nature of the ALADIN mutations. Thus, modifying genes/factors may be involved in the progression of this neurodegenerative disease. The lack of AAAS mutations in eight patients and negative linkage to chromosome 12q13 in three families are suggestive of genetic heterogeneity. To examine the cellular localization of ALADIN mutants causing triple A syndrome, we investigated nine different ALADIN-mutants: 2 nonsense (W84X, Q456X), 2 frameshift (F157fsX171, G397fsX414) and 5 point mutations (Q15K, L25P, H160R, S263P, L381R) by transfection experiments with green fluorescence protein. Mutants were predominantly localized in the cytoplasm, but also found in the nucleus indicating that ALADIN is essential for NPC targeting. To investigate physiological functions of ALADIN in vivo, we generated and analysed Aaas-/- knockout mice by homologous recombination in embryonic stem cells. Surprisingly, required animals lack any gross abnormality in adrenal and nervous system function. Further studies have to investigate the role of ALADIN at NPCs and to identify interacting proteins. Functional analyses of ALADIN may permit further understanding of its role for adrenocortical function and neurodevelopment.
Objective:To clarify the prevalence, long-term natural history and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series.Methods:Retrospective clinical, histological and genetic analysis of 132 pediatric and adult patients (2-58 years) followed-up for several decades.Results:The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity and scoliosis (86.1%, from 8.9±4 years), with relatively-preserved limb strength and previously-unreported ophthalmoparesia in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic CNV, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p=0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% cases, systematic functional decline from the end of the third decade and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations and body mass abnormalities, which correlated with disease severity. Finally, we propose a set of severity criteria, provide quantitative data for outcome identification and establish a need for age stratification.Conclusion:Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not-so-rare disease.
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