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    Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

    Nat Genet. 2011 Mar 6. [Epub ahead of print]

    These two articles demonstrate that Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss, results from gain of function mutations in the gene for NOTCH2.
    Authors: Isidor B, Lindenbaum P, Pichon O, et. al

    Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.

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