Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation
Dalit Modan-Moses1, Bruria Ben-Zeev, Chen Hoffmann
1Pediatric Endocrinology Unit, Division of Pediatrics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. dmodan@sheba.health.gov.il
Context:
Mutations in MRAP, an interacting partner of the ACTH receptor, have been shown recently to cause familial glucocorticoid deficiency (FGD) in kindreds with confirmed FGD and no ACTH receptor mutations.
Objective:
We describe a Jewish-Ethiopian family with FGD caused by a novel MRAP mutation.
Patients:
Our index patient presented at the age of 19 months with hypocortisolism, severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Before the definite diagnosis was made, a female sibling was born in another hospital and succumbed during the neonatal period due to sepsis and adrenal crisis.
Methods:
DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient. The DAX-1, ACTH receptor (MC2R), and MRAP genes were analyzed.
Results:
The index patient was diagnosed with FGD and was found to be homozygous for a novel MRAP mutation, a seven-base deletion in exon 3 of the MRAP gene. This deletion causes a frame shift, resulting in a stop codon after 23 amino acids (L31X). Postmortem analysis of fibroblasts obtained from the female patient revealed that she harbored the same mutation.
Conclusions:
This is the first report of MRAP mutations after the recent identification of the gene. Whether the novel MRAP mutation described by us is associated with a particularly severe phenotype remains to be investigated.
Insights
A novel mutation in the MRAP gene caused familial glucocorticoid deficiency (FGD) in an Ethiopian-Jewish family. This genetic finding highlights MRAP’s role in adrenal development and underscores the importance of genetic testing for rare endocrine disorders.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Mutations in melanocortin 2 receptor accessory protein (MRAP) have been identified as a cause of familial glucocorticoid deficiency (FGD).
- MRAP interacts with the ACTH receptor, playing a crucial role in adrenal steroidogenesis.
Purpose of the Study:
- To investigate the genetic basis of FGD in a Jewish-Ethiopian family.
- To identify novel mutations in the MRAP gene associated with FGD.
Main Methods:
- Genetic analysis of the DAX-1, ACTH receptor (MC2R), and MRAP genes.
- DNA extraction from peripheral blood and fibroblast samples.
- Homozygosity testing for identified mutations.
Main Results:
- A novel seven-base deletion in exon 3 of the MRAP gene was identified in the index patient, causing a premature stop codon (L31X).
- The index patient presented with severe hypocortisolism and neurological deficits.
- The same MRAP mutation was confirmed in a deceased sibling, indicating a severe phenotype.
Conclusions:
- This study reports the first MRAP mutation in the Jewish-Ethiopian population.
- The identified MRAP mutation is associated with a severe form of familial glucocorticoid deficiency.
- Further research is needed to fully understand the genotype-phenotype correlation of this novel MRAP mutation.
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