cqvip:Background: Transcranial ultrasound may be used to detect increased iron leve ls of the substantia nigra (SN) in patients with Parkinson disease (PD) and in c ontrol subjects. It is not known whether iron accumulation in PD is a primary or secondary phenomenon. However, sequence variations in genes involved in iron me tabolism have been linked to basal ganglia disorders. One of these is ceruloplas min (Cp), which is vitally involved in iron transport across the cell membrane. Methods: One hundred seventy-six patients with PD according to the UK Brain Ba nk criteria and 180 ethnically matched control subjects, who were previously exa mined for SN iron signal changes by transcranial ultrasound, were examined for m utations in the Cp gene using denaturing high-performance liquid chromatograph y and subsequent sequencing for verification of unequivocal signals. Immunohisto chemistry of PD midbrains was performed to examine the presence of Cp in Lewy bo dies. Results: Five novel missense variations were detected. One of these (I63T) was found in a single PD patient. A known variation (D554E)was significantly as sociated with PD and the ultrasound marker for increased SN iron levels. Moreove r, a third sequence variation (R793H) was found to segregate with the ultrasound marker for increased iron levels in patients an d control subjects. Immunohistochemistry demonstrated that Cp co-localizes wit h Lewy bodies in PD. Conclusions: Detection of sequence variations in a single P arkinson disease (PD) patient or associated with the ultrasound marker for incre ased substantia nigra iron levels and the presence of ceruloplasmin (Cp) immunor eactivity in Lewy bodies underline a suspected role for Cp in the pathogenesis o f PD. Further functional analyses are warranted to investigate whether these var iations are causally linked to the complex pathogenesis of PD in a subset of cas es.
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