Spectrum of Mutations of the AAAS Gene in Allgrove Syndrome: Lack of Mutations in Six Kindreds with Isolated Resistance to Corticotropin

• Published in: The journal of clinical endocrinology and metabolism 2001-11, Vol.86 (11), p.5433-5437
• Main Authors: Sandrini, Fabiano, Farmakidis, Constantine, Kirschner, Lawrence S., Wu, Shao-Ming, Tullio-Pelet, Anna, Lyonnet, Stanislas, Metzger, Daniel L., Bourdony, Carlos J., Tiosano, Dov, Chan, Wai-Yee, Stratakis, Constantine A.
• Format: Article
• Language: English
• Subjects: Adrenocorticotropic Hormone - blood; Adrenocorticotropic Hormone - physiology; Biological and medical sciences; Complex syndromes; DNA - genetics; DNA - isolation & purification; Endocrinopathies; Exons - genetics; Genotype; Glucocorticoids - deficiency; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); Introns - genetics; Medical genetics; Medical sciences; Mutation - genetics; Nerve Tissue Proteins; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Nuclear Pore Complex Proteins; Phenotype; Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Syndrome; Thyrotropin - physiology; Tropical medicine
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.11.8037

Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: isolated ACTH resistance (iACTHR), which may be caused by inactivating mutations of the ACTH receptor (the MC2R gene) or mutations in an as yet unknown gene(s), and Allgrove syndrome (AS). The latter is also known as triple-A syndrome (MIM 231550). In three large cohorts of AS kindreds, the disease has been mapped to chromosome 12; most recently, mutations in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insufficiency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect of the TSH receptor. Four AS families were of mixed extraction from Puerto Rico (PR); most of the remaining six families were Caucasian families from North America (NA). Sequencing analysis found no MC2R genetic defects in any of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mutations. The previously reported IVS14+1G→A splice donor mutation was found in all PR families, apparently due to a founder effect; one NA kindred was heterozygous for this mutation. In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene. No other heterozygote or transmitting parent had any phenotype that could be considered part of AS. The IVS14+1G→A mutation results in a premature termination of the predicted protein; although it was present in all PR families (in the homozygote state in three of them), there was substantial clinical variation between them. One PR family also carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G→A; the proband was a compound heterozygote. A novel point mutation, 43C→A(Gln15Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS kindred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservation of stability of ALADIN β-strands, whereas the splicing mutation in exon 11 may interfere with the formation of WD repeats in this molecule. We conclude that 1) AAAS does not appear to be frequently mutated in families with iACTHR; 2) AAAS is mutated in AS families from PR (that had previously been mapped to 12q13) and NA; and, 3) there is