Familial Glucocorticoid Deficiency (FGD) [OMIM #202200] is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex to stimulate glucocorticoid production. It has previously been linked to mutations in the ACTH receptor (ACTHR) [FGD type 1] and a locus on chromosome 8q, but 70% of cases have no known cause. The aim of this study was to identify additional loci and genes for FGD using a linkage mapping strategy. One consanguineous family (A) having three affected and two unaffected individuals was studied initially. After exclusion of the ACTHR and 8q loci using microsatellite markers, genomic DNA samples were analysed using the Affymetrix GeneChip Mapping 10K array in which SNPs are positioned on average every 210 kb throughout the whole human genome. This revealed a region of homozygosity 1.9 Mb in size on chromosome 21, which was confirmed by microsatellite mapping. The same region also displayed homozygosity in another consanguineous family (B). Here we report identification of disease-associated mutations in an uncharacterised gene located within this interval. We identified three splice donor site mutations, IVS1ds+1 G>T (family A) and IVS1ds+1 G>C (family B and 1 other family), IVS1ds+3 insT in two families and a rare mutation changing the initiator methionine ATG to ATA (M1I) in a further five families. RT-PCR of multiple human tissues showed a limited expression pattern (adrenal, adipose tissue and skin) similar to that for ACTHR. The striking concordance in expression of this gene and the ACTHR, combined with the observation that deficiency of either gene results in an effectively identical clinical syndrome, suggests that this gene is intimately involved in ACTHR function or expression.
01 - 03 Nov 2004
Society for Endocrinology