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      A Novel AAAS Gene Mutation (p.R194X) in a Patient with Triple A Syndrome

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          Objective: The clinical and molecular data of a patient with triple A syndrome are reported. Patient: A 21-year-old male who was diagnosed for adrenal insufficiency at the age of 2 years after a severe attack of adrenal crisis. At the age of 4 years, achalasia and alacrima were diagnosed. Puberty started at the age of 17 years. At the same time, symptoms of central, peripheral, and autonomic nervous system dysfunction were noted. Later on, at the age of 20 years, a bone age delay of 6 years and severe osteoporosis was diagnosed. Results: A compound heterozygous AAAS mutation consisting of two mutations was found: a C > T transition in exon 7 resulting in a change of arginine at amino acid position 194 into a stop codon (Arg194X) at one allele, and a C > T transition in exon 12 resulting in a change of glutamine at amino acid position 387 into a stop codon (Gln387X) on the other allele. Conclusion: The mutation in exon 7 (p.R194X) of the AAAS gene is a novel mutation which has not been found in any other family so far, whereas the second was already found in some other families. This case adds to the clinical and molecular spectrum of triple A syndrome and may provide a new insight into the functions of AAAS gene.

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          Most cited references 22

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          The WD repeat: a common architecture for diverse functions.

          Our knowledge of the large family of proteins that contain the WD repeat continues to accumulate. The WD-repeat proteins are found in all eukaryotes and are implicated in a wide variety of crucial functions. The solution of the three-dimensional structure of one WD-repeat protein and the assumption that the structure will be common to all members of this family has allowed subfamilies of WD-repeat proteins to be defined on the basis of probable surface similarity. Proteins that have very similar surfaces are likely to have common binding partners and similar functions.
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            Posterior vitreous detachment: evolution and complications of its early stages.

             Mark Johnson (2010)
            To summarize emerging concepts regarding the onset and progression, traction effects, and complications of the early stages of age-related posterior vitreous detachment (PVD). Interpretive essay. Review and synthesis of selected literature, with clinical illustrations, interpretation, and perspective. Imaging of the vitreoretinal interface with optical coherence tomography has shown that PVD begins in the perifoveal macula. Recent longitudinal studies have demonstrated conclusively that early PVD stages persist chronically and progress slowly over months to years. Vitreous traction forces resulting from perifoveal PVD with a small vitreofoveolar adhesion (500 microm or less) may cause localized cystoid foveal thickening or one of several macular hole conditions. Traction associated with larger adhesion zones may cause or exacerbate a separate group of macular disorders. Ultrastructural studies suggest that epiretinal membrane develops from cortical vitreous remnants left on the retinal surface after PVD and plays an important role in traction vitreomaculopathies. Age-related PVD is an insidious, chronic event that begins in the perifoveal macula and evolves over a prolonged period before vitreopapillary separation. Although asymptomatic in most individuals, its early stages may be complicated by a variety of macular and optic disc pathologic features, determined in part by the size and strength of the residual vitreoretinal adhesion. (c) 2010 Elsevier Inc. All rights reserved.
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              Mutant WD-repeat protein in triple-A syndrome.

              Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2006
                09 May 2006
                : 65
                : 4
                : 171-176
                aDepartment of Internal Medicine, Division of Endocrinology, Clinical Hospital Center Zagreb and Zagreb University School of Medicine, Zagreb, Croatia; bChildren’s Hospital, Technical University Dresden, Dresden, Germany
                92003 Horm Res 2006;65:171–176
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 2, References: 28, Pages: 6
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