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The disease locus for triple-A syndrome (231550), which results in life-threatening hypoglycemic episodes and severe feeding difficulties related to achalasia and gastric atonia, was localized to 12q13 (Weber et al., 1996; Stratakis et al., 1997). Using fine-mapping based on linkage disequilibrium in North African inbred families, Tullio-Pelet et al. (2000) identified a short ancestral haplotype on 12q13 (less than 1 cM), sequenced a BAC contig encompassing the triple-A minimal region, and identified a novel gene designated AAAS, encoding a 547-amino acid protein, called aladin, that was mutant in affected individuals. Aladin (for 'alacrima-achalasia-adrenal insufficiency neurologic disorder') belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in the triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures pointed to a role in the normal development of the peripheral and central nervous systems.
By peptide mass fingerprint spectra, Dreger et al. (2001) identified adracalin in a TX100-resistant fraction of nuclear envelope proteins isolated from a mouse neuroblastoma cell line. Mouse adracalin is a nonmembrane-spanning protein and has an apparent molecular mass of 60 kD.
Sandrini et al. (2001) investigated 4 families with isolated ACTH resistance (202200) and 6 with Allgrove syndrome (triple-A syndrome; 231550). Four triple-A syndrome families were of mixed extraction from Puerto Rico; most of the remaining 6 families were Caucasian families from North America. No kindreds with ACTH resistance, but all of the triple-A syndrome families, had AAAS mutations. The IVS14+1G-A donor splice mutation (605378.0005) was found in all Puerto Rican families, apparently due to a founder effect; one North American kindred was heterozygous for this mutation. One Puerto Rican family carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G-A (605378.0008); the proband was a compound heterozygote. A gln15-to-lys point mutation (605378.0006) was identified in homozygosity in a Canadian triple-A syndrome kindred with a milder phenotype. The authors found significant clinical variability between patients with the same AAAS defect.
In 9 patients with triple-A syndrome, Handschug et al. (2001) found 8 different homozygous and compound heterozygous mutations in the AAAS gene (e.g., 605378.0006-605378.0007), most of which predicted premature termination of the protein. Northern blot analysis revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple-A syndrome. The predicted protein belongs to the family of WD repeat-containing proteins, which exhibit a high degree of functional diversity, including regulation of signal transduction, RNA processing, and transcription (Neer et al., 1994; see also 604737).
Cronshaw and Matunis (2003) showed that targeting of aladin to nuclear complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport, is essential for the function of aladin. They found that a variety of disease-associated mutations in the AAAS gene caused a failure of aladin to localize to NPCs, and that these mutant aladin proteins were found predominantly in the cytoplasm. Microscopic analysis of cells from a triple-A patient revealed no morphologic abnormalities of the nuclei, nuclear envelopes, or NPCs. These findings indicated that defects in NPC function, rather than structure, give rise to triple-A syndrome. Cronshaw and Matunis (2003) proposed that aladin plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance and/or development of certain tissues.
In a 75-year-old man with triple-A syndrome, Bitetto et al. (2019) identified a homozygous missense mutation in the AAAS gene (R155H; 605378.0011). RT-PCR analysis in patient fibroblasts showed decreased expression of AAAS isoform 1 and upregulation of AAAS isoform 2. Overexpression of AAAS isoform 1 in the fibroblasts did not normalize AAAS2 isoform expression. Treatment of patient fibroblasts with cycloheximide did not restore gene expression of AAAS isoform 1, indicating that nonsense-mediated decay likely did not play a role in decreased expression. Transcript analysis in postmortem frontal cortex, cerebellum, and spinal cord tissue from the patient showed decreased expression of AAAS isoform 1 and no change in expression of AAAS isoform 2. Aladin protein expression was reduced in patient nervous system tissues but was not significantly mislocalized in the cells. Aladin expression was also reduced in patient fibroblasts, and subcellular fraction showed that it localized appropriately to the membrane fraction.
Goizet et al. (2002) reported a Portuguese woman who presented at age 33 years with progressive bulbospinal amyotrophy and autonomic dysfunction associated with typical features of the triple-A syndrome, which had been present since birth. She was found to be homozygous for the R478X mutation.
In a family from France with triple-A syndrome (AAAS; 231550), Tullio-Pelet et al. (2000) found a splice site mutation in the acceptor site of intron 4 of the AAAS gene. The IVS4-2A-G mutation resulted in the retention of intron 4 in the mutant mRNA and in a premature translation termination 47 codons downstream from exon 4.
Genin et al. (2004) developed a likelihood-based method for estimating the age of the most recent common ancestor of individuals bearing a given mutation in whom a founder effect is suspected. The authors analyzed haplotype information from 9 unrelated patients of North African origin with the IVS14+1G-A mutation and found an age estimate of approximately 1,000 to 1,175 years, which corresponds to a period of large migrations into North Africa from the Arabian peninsula.
Chang et al. (2008) reported 2 sibs from a Mexican American family with Allgrove syndrome who were compound heterozygous for the IVS14+1G-A mutation and another mutation in the AAAS gene, inherited from their father and mother, respectively. Paternal haplotype analysis suggested that the mutation was derived from an ancestral North African chromosome carrying the original founder mutation, consistent with historically known migration patterns of North African individuals into Spain approximately 1,000 years ago, followed by the colonization of Central and South America by Spanish explorers.
Prpic et al. (2003) described an 18-year-old woman with achalasia and mild neurologic abnormalities who was found to be homozygous for the S263P mutation, She was the second child of nonconsanguineous parents and presented at the age of 10 years with recurrent vomiting. Achalasia was diagnosed and surgically corrected at the age of 14 years, following which she had no swallowing problems. Tear production, as determined by the Schirmer test, was normal. Repeated adrenal function tests showed normal results. Neurologic abnormalities included muscle atrophy, pes cavus, and a positive Babinski sign. She showed no dermatologic abnormalities.
In a 14-year-old girl with achalasia and alacrima (see 231550), Koehler et al. (2008) identified compound heterozygosity for 2 mutations in the AAAS gene: a 251G-A transition in exon 2 (605378.0010), resulting in aberrant splicing and lack of a transcript due to nonsense-mediated mRNA decay, and a 1288C-T transition in exon 14, resulting in a leu430-to-phe (L430F) substitution. Thus, the clinical picture resulted from the hemizygous L430F protein. Since in vitro functional expression studies showed that the L430F-mutant protein correctly localized to the nuclear pore complex, Koehler et al. (2008) concluded that the mutation must lead to impaired protein function. The patient had an unusual presentation with childhood-onset of a slowly progressive axonal neuropathy with conspicuous distal muscle atrophy and lack of adrenal insufficiency.
In a 75-year-old man with triple-A syndrome (AAAS; 231550), Bitetto et al. (2019) identified homozygosity for a c.464G-A transition (c.464G-A, NM_015665.6) in exon 6 of isoform 1 of the AAAS gene, resulting in an arg155-to-his (R155H) substitution at a highly conserved residue. The mutation was identified by Sanger sequencing and was not present in the 1000 Genomes Project and ExAC databases or in 1,000 Italian exomes. RT-PCR in patient fibroblasts showed decreased expression of AAAS isoform 1 and upregulation of AAAS isoform 2. Transcript analysis in postmortem frontal cortex, cerebellum, and spinal cord tissue from the patient showed decreased expression of AAAS isoform 1 and no change in expression of AAAS isoform 2. Aladin protein expression was reduced in patient nervous system tissues and, to a lesser extent, in patient fibroblasts.
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