Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams–Oliver Syndrome With Variable Cardiac Anomalies

Abstract

A dams-Oliver syndrome (AOS; MIM 100300) is a rare developmental disorder, characterized by a range of abnormalities that include cranial aplasia cutis congenita (ACC) and terminal transverse limb defects.1,2 The spectrum of defects observed implies dysregulation of multiple developmental pathways. Congenital heart defects (CHDs) have been reported in conjunction with AOS in ≤20% of cases and, when present, represent a serious mortality risk.3,4 Cardiac defects are also commonly associated with systemic structural vascular abnormalities, of which cutis marmorata telangiectatica congenita is the most frequently described.5 AOS primarily segregates as an autosomal dominant trait with variable phenotypic expression. A small number of kindreds are consistent with autosomal recessive disease gene transmission. In addition, sporadic cases with comparable clinical features indicate the occurrence of de novo mutations in causative disease genes.The molecular genetic basis of AOS appears heterogeneous and, to date, defects within 5 genes have been reported, providing limited insight as to the molecular mechanisms underlying these important aspects of early development. Mutations of the ARHGAP31 and DOCK6 genes underlie a proportion of AOS cases displaying autosomal dominant and recessive inheritance, respectively. 6,7 Both ARHGAP31 and DOCK6 regulate the activity of the Rho GTPases Cdc42 and Rac1, which cycle between active, GTP-bound and inactive, GDPbound states through the opposing modes of action of guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We have previously demonstrated that ARHGAP31 mutations cause AOS through a gain-of-function mechanism, which leads to an accumulation of inactive GTPase, disrupting Background-Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. Methods and Results-Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS.Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 m...

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

“…Recent studies suggest that activation of the NOTCH signaling pathway is related to radiation resistance in tumor cells (19)(20)(21). OncodriveROLE, a machine learning-based approach, indicated that the NOTCH1 p.Cys1374Tyr mutation, as detected in our study, is a "loss-of-function" mutation (22,23). Thus, in our case, loss-of-function in the NOTCH1 gene might have led to radiation sensitivity, resulting in the ability of cells harboring those mutations to be eradicated by radiotherapy.…”

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

“…Moreover, mutations in human EOGT have been reported in an autosomal recessive form of a human disease called AdamsOliver syndrome (55,56). Notably, mutations in several Notch pathway components cause an autosomal dominant form of the same disease (39,40,(57)(58)(59). Together, these reports provide strong evidence that O-GlcNAcylation might modulate Notch signaling.…”

The developmental biology of genetic Notch disorders

“…This rare genetic disorder can be autosomal dominant, autosomal recessive or caused by de novo mutations. The autosomal recessive forms are caused by mutations in EOGT, which encodes a component of the Notch pathway, or in DOCK6, which encodes a regulator of Rho GTPase signaling Shaheen et al, 2011Shaheen et al, , 2013Sukalo et al, 2015a,b), whereas the dominant forms are caused by mutations in NOTCH1, RBPJ or DLL4, all of which are Notch pathway components, or in ARHGAP31, which encodes another Rho GTPase regulator (Hassed et al, 2012;Isrie et al, 2014;Meester et al, 2015;Southgate et al, 2011Southgate et al, , 2015Stittrich et al, 2014). In the case of DLL4, it was noted that the disease-associated mutations are distributed throughout the ligand (Meester et al, 2015;Fig.…”