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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2
Journal of Clinical Endocrinology and Metabolism, Volume 95, No. 7, Year 2010
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Description
Background: 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. Copyright © 2010 by The Endocrine Society.
Authors & Co-Authors
Hughes, Claire R.
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Chung, Teng Teng
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Habeb, Abdelhadi M.
Saudi Arabia, Madinah
Maternity and Children Hospital
Kelestimur, Fahrettin
Turkey, Kayseri
Erciyes University, Faculty of Medicine
Clark, Adrian J.L.
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Metherell, Louise A.
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Statistics
Citations: 23
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1210/jc.2009-2731
ISSN:
0021972X
e-ISSN:
0021972X
Research Areas
Disability
Genetics And Genomics
Health System And Policy
Mental Health
Study Approach
Qualitative