Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families.

Abstract

Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid deficiency, high plasma ACTH levels, and a normal renin-aldosterone axis. Defects of the ACTH receptor have been suggested as a possible cause, and we have previously reported a number of novel mutations of the ACTH receptor gene in some, but not all, cases, suggesting that familial glucocorticoid deficiency may have a heterogeneous molecular etiology. Here we report the clinical features and ACTH receptor gene analysis in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other two patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family members. Human CRH tests in the parents of patients A and B showed normal cortisol and ACTH responses in the S74I, R128C, and I44M heterozygotes and exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.

The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor

“…Hypothyroidism was detected through the national neonatal screening program and showed high blood TSH and low total thyroxine (T4) values. These were confirmed by serum measurements of TSH greater than 100 mU/L (normal range 0.5-6) and free thyroxine (FT4) of 1.2-7.0 pmol/L (normal [11][12][13][14][15][16][17][18][19][20][21][22][23][24] prior to the institution of treatment with levothyroxine (LT4) (Fig. 1).…”

“…Eleven distinct point mutations of the ACTHR gene have been identified in patients with RACTH belonging to ten unrelated families (22)(23)(24)(25)(26)(27). Nine involve single amino acid substitutions and two produce truncated molecules.…”

Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs

“…30 Interestingly, MRAP was also the first GPCR accessory protein to be implicated in human disease. 59 While 25% of familial glucocorticoid deficiencies are related to mutations in the adrenocorticotropin receptor, [60][61][62][63] 20% are associated with mutations in MRAP. [64][65][66] Not only does this emphasize the importance of proper MC2 trafficking in human health, but it also emphasizes the role of MRAP in this phenomenon.…”

Linkage of one gene for familial glucocorticoid deficiency type 2 (FGD2) to chromosome 8q and further evidence of heterogeneity

“…FGD is an heterogeneous disorder, in most cases being inherited as an autosomal recessive disease that was first reported as a distinct new entity by Shepard et al in 1959. Some of the patients with FGD have mutations inside the coding region of the ACTH receptor (MC2R) gene (Clark et al 1993;Naville et al 1996;Tsigos et al 1993Tsigos et al , 1995Weber et al 1995) and have been classified as FGD type 1. However, more than half of the patients do not have mutations within the MC2R gene (Weber et al 1995) and have been denoted as FGD type 2.…”

“…Some of the patients with FGD have mutations inside the coding region of the ACTH receptor (MC2R) gene (Clark et al 1993;Naville et al 1996;Tsigos et al 1993Tsigos et al , 1995Weber et al 1995) and have been classified as FGD type 1. However, more than half of the patients do not have mutations within the MC2R gene (Weber et al 1995) and have been denoted as FGD type 2. Although FGD type 1 and type 2 patients exhibit a nearly indistinguishable phenotype, the genotype appears to be heterogeneous (Naville et al 1998;Weber and Clark 1994).…”