Southgate Laura, Sukalo Maja, Karountzos Anastasios S V, Taylor Edward J, Collinson Claire S, Ruddy Deborah, Snape Katie M, Dallapiccola Bruno, Tolmie John L, Joss Shelagh, Brancati Francesco, Digilio M Cristina, Graul-Neumann Luitgard M, Salviati Leonardo, Coerdt Wiltrud, Jacquemin Emmanuel, Wuyts Wim, Zenker Martin, Machado Rajiv D, Trembath Richard C
Division of Genetics & Molecular Medicine, King's College London, Faculty of Life Sciences & Medicine, Guy's Hospital, London, United Kingdom.
Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
Circ Cardiovasc Genet. 2015 Aug;8(4):572-581. doi: 10.1161/CIRCGENETICS.115.001086. Epub 2015 May 11.
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.
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 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway.
These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.
亚当斯 - 奥利弗综合征（AOS）是一种罕见的疾病，其特征为先天性肢体缺陷和头皮皮肤发育不全。在部分病例中，明显的心脏受累也较为常见。尽管近期对AOS的遗传基础有了一定进展，但对于大多数受影响的个体，潜在的分子缺陷仍未明确。本研究旨在确定AOS的新遗传决定因素。
对12名临床诊断为AOS的先证者进行了全外显子测序。分析发现2个家系中存在新的杂合性截短NOTCH1突变（c.1649dupA和c.6049_6050delTC），在这些家系中AOS作为常染色体显性性状进行分离。在对52名无关的AOS患者队列进行筛查时，我们又检测到另外8个独特的NOTCH1突变，包括3个新生氨基酸替代，均位于配体结合域内。在NOTCH1阳性的先证者及其受影响的家庭成员中，47%（8/17）存在先天性心脏异常。在携带NOTCH1细胞外结构域突变的受试者的白细胞衍生RNA中，我们观察到NOTCH1表达显著降低，提示细胞机制导致突变mRNA转录本不稳定并降解。对诱变的NOTCH1错义构建体进行瞬时转染也显示基因表达显著降低。突变NOTCH1的表达与Notch靶基因HEY1和HES1的下调相关，表明NOTCH1相关的AOS是通过Notch信号通路失调而产生的。
这些发现突出了NOTCH1在一系列发育异常（包括心脏缺陷）中的关键作用，并提示NOTCH1单倍体不足可能是这组疾病的分子机制。
