Spectrum of mutations of the AAAS gene in Allgrove syndrome: Lack of mutations in six kindreds with isolated resistance to corticotropin

Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance c onsists of two distinct genetic syndromes that are both inherited as autoso mal recessive traits: isolated ACTH resistance (iACTHR), which may be cause d by inactivating mutations of the ACTH receptor (the MC2R gene) or mutatio ns 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, muta tions in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insuff iciency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect o f 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 a ny of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mu tations. The previously reported 1VS14+1G -->A splice donor mutation was fo und 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 fa iled to identify a deletion or other rearrangements of the AAAS gene. No ot her heterozygote or transmitting parent had any phenotype that could be con sidered part, off AS. The IVS14+1G -->A mutation results in a premature ter mination of the predicted protein; although it was present in all PR famili es (in the homozygote state in three of them), there was substantial clinic al 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 comp ound heterozygote. A novel point mutation, 43C -->A(Gln(16)Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS ki ndred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservati on of stability of ALADIN beta -strands, whereas the splicing mutation in e xon 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 significant clinical variab ility between patients with the same HAAS defect.