Novel In-Frame Deletion Mutation in NOTCH1 in a Chinese Sporadic Case of Adams-Oliver Syndrome

DNA and Cell Biology
Suqiu HuangYurong Wu

Abstract

Adams-Oliver syndrome (AOS) is a rare hereditary disorder characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. The etiology of AOS has remained largely unknown, although mutations in the notch receptor 1 (NOTCH1) gene are most common genetic alteration associated with this disease. In this study, we aimed to identify the case of a 6-year-old boy, who presented with large ACC of the scalp and aortic valve stenosis, suggesting the possibility of AOS. Whole-exome sequencing identified a novel, de novo, in-frame deletion in the NOTCH1 gene (NOTCH1 c.1292_1294del, p.Asn431del) in the patient. The p.Asn431del variant was evaluated by several in silico analyses, which predicted that the mutant was likely to be pathogenic. In addition, molecular modeling with the PyMOL Molecular Graphics System suggested that the NOTCH1-N431del destabilizes calcium ion chelation, leading to decreased receptor-ligand binding efficiency. Quantitative reverse transcription PCR showed further significant downregulation of the Notch target genes, hes-related family bHLH transcription factor with YRPW motif 1 (HEY1) and hes family bHLH transcription factor 1 (HES1), suggesting that this mutation causes disease through dysregul...Continue Reading

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Citations

Oct 13, 2020·Tissue Engineering. Part B, Reviews·Kathleen Zohorsky, Kibret Mequanint

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Methods Mentioned

BETA
GTPase
reverse transcription PCR
X-ray

Software Mentioned

PyMOL Molecular Graphics System
Picard
Wheeler Aligner ( BWA )
MutationTaster
Genome Analysis Toolkit ( GATK +
PROVEAN
SAM
MutPred
Burrows

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