HCS is an autosomal dominant disorder, only one parent with the defective gene is needed to pass the disorder to the offspring.Mutations within the last coding exon of NOTCH2 that remove the PEST domain and escape the nonsense-mediated mRNA decay have been shown to be the main cause of Hajdu–Cheney syndrome. The NOTCH2 gene plays a very important role in skeletogenesis. Mutations of NOTCH2 that seem to cause HCS occur in the last coding exon of the gene (exon 34). These mutations remove PEST domains, which mediate proteosomal destruction of the protein. These PEST domains are removed due to the premature stop codon in the amino acid sequence. All HCS alleles are observed to have premature protein destruction before the PEST sequence is fully translated. The result is a mature NOTCH2 gene with a partially completed PEST sequence. In some cases, no PEST sequence at all is seen. This leads to the no proteosomal destruction of the protein.The NOTCH2 gene is ubiquitously expressed in all embryonic tissue. When researching HCS in mice, the homozygous deletion of NOTCH2 leads to death. This observation is important because it explains how the HCS phenotype is not isolated to only one system of the body. NOTCH2 is also shown to regulate RANK-L osteoclastogenesis, which is the production of functional osteoclasts. Osteoclasts are the component that breaks bone down. This is why bone loss is observed in HCS patients, due to the overactivation of RANK-L.

Pathogenesis
The mechanism thought to cause HCS is an abnormality in osteoblast and osteoid function.
Retinal dysplasia in other animals
Cats - Retinal dysplasia occurs in utero or in newborns infected with feline leukemia virus or feline panleukopenia, which cause necrosis and disorganization of the retina. It appears as folds and rosettes. Cattle - Retinal dysplasia occurs in utero through infection with bovine viral diarrhea. It is also inherited in Shorthorns and Herefords. Both forms often cause retinal detachment. Sheep - Retinal dysplasia occurs by in utero infection with bluetongue disease. Horses - Retinal dysplasia is bilateral, not inherited, and appears as multifocal or geographic disease. It is usually accompanied by other eye problems. Chickens

See also
Progressive retinal atrophy


== References ==