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Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2 Hughes CR; Chung TT; Habeb AM; Kelestimur F; Clark AJ; Metherell LAJ Clin Endocrinol Metab 2010[Jul]; 95 (7): 3497-501BACKGROUND: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor [melanocortin 2 receptor (MC2R)] or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. Typically, type 2 patients present early (median age, 0.1 yr), and no patient reported to date has presented after 1.6 yr. AIM: The aim of this study was to investigate the cause of disease in two families with late-onset FGD. PATIENTS: The proband in family 1 was diagnosed at age 4 yr. Family review revealed two older siblings with undiagnosed FGD. One sibling was well, whereas the second had cerebral palsy secondary to hypoglycemic seizures. The proband in family 2 was diagnosed at age 18 yr with symptoms of fatigue, weight loss, and depression. METHODS: The coding exons of MC2R and MRAP were sequenced. ACTH dose-response curves were generated for MC2R when transfected with wild-type or mutant MRAP constructs using HEK293 cells. MC2R trafficking with both mutant MRAPs was investigated using immunocytochemistry. RESULTS: MRAP gene analysis identified two novel homozygous missense mutations, c.175T>G (pY59D) in family 1 and c.76T>C (p.V26A) in family 2. In vitro analysis showed that the Y59D mutant had significant impairment of cAMP generation, and both mutants caused a shift in the dose-response curve to the right when compared to wild type. Immunocytochemistry showed normal trafficking of MC2R when transfected with both mutant MRAPs, indicating a probable signaling defect. CONCLUSION: These results indicate that missense MRAP mutations present with a variable phenotype of ACTH resistance and can present late in life.|Adrenal Gland Diseases/*genetics[MESH]|Adult[MESH]|Child[MESH]|Female[MESH]|Fluorescent Antibody Technique[MESH]|Glucocorticoids/*deficiency/genetics[MESH]|Humans[MESH]|Male[MESH]|Membrane Proteins/*genetics[MESH]|Microscopy, Confocal[MESH]|Mutation, Missense/*genetics[MESH]|Pedigree[MESH] |
