Mutations in NOTCH2 in families with Hajdu-Cheney syndrome

Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Canada.
Human Mutation (Impact Factor: 5.14). 10/2011; 32(10):1114-7. DOI: 10.1002/humu.21546
Source: PubMed


Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis.

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    • "Mutations in NOTCH2 have previously been observed in Alagille syndrome, a multisystem monogenic disorder in which the majority of affected subjects harbor mutations in the gene encoding the Notch ligand JAG1 (12). However, there are substantial differences between Alagille syndrome and HCS in attributes including cholestasis, renal problem, and facial dysmorphologies (13). "
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    ABSTRACT: A 21-year-old man with diabetic ketoacidosis (DKA) displayed short and clubbed fingers and marked eyebrow, which are typical of Hajdu-Cheney Syndrome (HCS). Laboratory findings confirmed type 1 diabetes mellitus (DM). After conservative care with hydration and insulin supply, metabolic impairment was improved. Examinations of bone and metabolism revealed osteoporosis and craniofacial abnormalities. The mutation (c.6443T>G) of the NOTCH2 gene was found. The patient was diagnosed with HCS and DM. There may be a relationship between HCS and DM, with development of pancreatic symptoms related to the NOTCH2 gene mutation.
    Full-text · Article · Nov 2013 · Journal of Korean medical science
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    • "Approaches like the Cohort Allelic Sums Test (CAST) (Morgenthaler and Thilly, 2007) and Combined Multivariate and Collapsing (CMC) method (Li and Leal, 2008) aggregate the rare variants seen within a gene or a pathway to mitigate this, but the applicability of association-based methods remains extremely limited for small cohorts. The alternative approach of prioritizing disease-causing single nucleotide variants (SNVs) based on their population frequency, conservation and the type of change (radical versus conservative amino acid change, introduction of a stop codon, etc.) has been extremely effective at identifying causal non-synonymous mutations in a number of Mendelian disorders, including Charcot– Marie–Tooth neuropathy (Lupski et al., 2010), Hajdu–Cheney syndrome (Majewski et al., 2011a) and Miller syndrome (Ng et al., 2009). In this approach, the variants identified in the genome are filtered to those with low allele frequencies (common variants are unlikely to cause rare disorders) and are sorted based on a 'harmfulness' score generated by tools such as PolyPhen, SIFT or PANTHER (Adzhubei et al., 2010; Ng and Henikoff, 2003; Thomas et al., 2003). "
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    ABSTRACT: Motivation: The prioritization and identification of disease-causing mutations is one of the most significant challenges in medical genomics. Currently available methods address this problem for non-synonymous single nucleotide variants (SNVs) and variation in promoters/enhancers; however, recent research has implicated synonymous (silent) exonic mutations in a number of disorders.Results: We have curated 33 such variants from literature and developed the Silent Variant Analyzer (SilVA), a machine-learning approach to separate these from among a large set of rare polymorphisms. We evaluate SilVA's performance on in silico 'infection' experiments, in which we implant known disease-causing mutations into a human genome, and show that for 15 of 33 disorders, we rank the implanted mutation among the top five most deleterious ones. Furthermore, we apply the SilVA method to two additional datasets: synonymous variants associated with Meckel syndrome, and a collection of silent variants clinically observed and stratified by a molecular diagnostics laboratory, and show that SilVA is able to accurately predict the harmfulness of silent variants in these datasets.Availability: SilVA is open source and is freely available from the project website: silvaContact: Supplementary information: Supplementary data are available at Bioinformatics online. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected] /* */
    Full-text · Article · Jun 2013 · Bioinformatics
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    • "The dysregulation of Notch signaling underlies the pathogenesis of various developmental disorders and cancers. Recently, Hajdu-Cheney syndrome, a rare skeletal disorder characterized by osteoporosis, has been found to be caused by gain-of-function mutations in NOTCH2.3, 4 It has long been well established that loss of function (LOF) in DLL3 or JAGGED1, both Notch ligands, or loss of function in HES7, LFNG, or MESP2, Notch downstream target genes, can lead to a spectrum of vertebral patterning defects such as those seen in Alagille syndrome or in spondylocostal dysostosis types I, II, and III.5 Interestingly, patients with these disorders also show symptoms attributable to alteration of cartilage and bone homeostasis, eg, short stature and low bone mass.6 "
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    ABSTRACT: Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by "butterfly" vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj deficient Notch GOF mice compared to Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis. © 2012 American Society for Bone and Mineral Research.
    Full-text · Article · Mar 2013 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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