A mutant mouse model of Hajdu-Cheney syndrome | 17813
Journal of Genetic Syndromes & Gene Therapy

Journal of Genetic Syndromes & Gene Therapy
Open Access

ISSN: ISSN: 2157-7412

+44 1223 790975

A mutant mouse model of Hajdu-Cheney syndrome

Annual Congress on Rare Diseases & Orphan Drugs

October 26-27, 2016 Chicago, USA

Canalis E

UConn Health, USA

Posters & Accepted Abstracts: J Genet Syndr Gene Ther

Abstract :

Hajdu-Cheney syndrome (HCS) is a rare but devastating genetic disease characterized by craniofacial developmental abnormalities, acro-osteolysis, severe osteoporosis with fractures and sudden death. HCS is associated with a gain-of-function of NOTCH2, where point mutations in exon 34 lead to a truncated and stable NOTCH2 protein product. To study and understand HCS, we created a mouse model harboring a Notch2 mutant allele reproducing the mutation found in subjects with HCS. The 6955C>T mutation in mice created a stop codon at glutamic acid 2319, upstream the PEST domain which is required for Notch degradation. Sequences necessary for Notch2 transcriptional activity are preserved. The 6955C>T mutation was introduced into the Notch2 locus by homologous recombination, verified by DNA sequencing and mice characterized following removal of the selection cassette. Notch target genes were induced in tissues of HCS-Notch2 mice, demonstrating Notch signal activation. Homozygous HCS-Notch2 mutants exhibited newborn lethality, whereas heterozygous mice had pronounced bone loss. Micro-computed tomography of HCSNotch2 mutants revealed a 50-55% decrease in cancellous bone volume and markedly decreased connectivity. Cortical thickness, total and cortical cross-sectional areas were decreased by 20-40%. Histomorphometry revealed increased osteoclast number and bone resorption and only a modest decrease in bone formation. Bone marrow mononuclear cells had an increased capacity to form multinucleated osteoclastsin response to M-CSF and RANK-L, explaining the enhanced bone resorption. Osteoblast cultures exhibited increased RANK-L mRNA. In conclusion, a genetically engineered HCS mutant mouse model recreates the human disease and exhibits pronounced osteopenia due to an increased osteoclastogenesis and bone resorption. For the first time, the skeletal pathogenesis of HCS is explained.

Biography :