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Endocrine Abstracts (2021) 77 P134 | DOI: 10.1530/endoabs.77.P134

1QMUL, London, United Kingdom; 2Masonic Medical Centre for Children, Coimbatore, India

Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency with retention of normal mineralocorticoid production. FGD causing mutations in the MC2R accessory protein, MRAP, often occur at the canonical donor splice-site of intron 3, presumed to result in skipping of the first coding exon with unknown consequences at the protein level. DNA from three patients (0 - 6 months) with high ACTH and/or low cortisol levels underwent whole exome sequencing. The proband in family 1 (P1) presented at 13 months and had a hyperpigmented sibling who died in neonatal period due to adrenal failure. Patient 2 (P2) had a family history of adrenal insufficiency and was hyperpigmented at birth and patient 3 (P3) had diffuse hyperpigmentation in the early neonatal period and low cortisol on formal testing at 16m. Variants were confirmed using Sanger sequencing and predicted splice-site mutations were investigated using an in vitrosplicing assay. Homozygous mutations in MRAP were identified in all three cases. Previously described, c.106+1delG (P1) and c.106+2dupT (P2) at the canonical donor splice-site of intron 3, were identified, with the former predicted to destroy the splice site and the latter to weaken it. These mutations in vitroresulted in the complete skipping of exon 3 with unknown consequence to the protein (p.?). A novel homozygous mutation in intron 4, c.206+5G>T was identified in P3 but was not predicted to alter splicing. However, in vitro, this mutation negates the canonical donor splice site and creates two different alternative sites, both resulting in frameshifts and predicted early termination of the protein (p.Val44fs*50, p.Asn70fs*92). Splice prediction protocols, though largely effective for variants within 2bp of exon/intron boundaries may not predict the true outcome of more distant base change(s), highlighting the necessity of functional assays to assign pathogenicity to them.

Volume 77

Society for Endocrinology BES 2021

Edinburgh, United Kingdom
08 Nov 2021 - 10 Nov 2021

Society for Endocrinology 

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