New mutation (RA2P) of the parkin gene in the ubiquitinlike domain associated with parkinsonism

Objective: To investigate the association between parkin gene mutations and parkinsonism in an Italian family in which three of 12 siblings born to fi rst-degree consanguineous parents had early-onset parkinsonism. Background: Several deleting or truncating mutations as well as missense mutations of the parkin gene were associated with early-onset parkinsonism. Method: Thre e brothers were examined clinically at several stages of the disease: Singl e-strand conformational polymorphism analysis was done on the parkin gene o f 32 members of the family. Samples showing mobility shifts were considered far mutation analysis. Results: Direct DNA sequencing revealed a novel hom ozygous amino acid substitution, Arg42Pro, in all three patients compared w ith a control DNA sample. The mutation occurred in the ubiquitinlike domain at the N-terminal of the protein. The patients did not display the clinica l hallmarks previously seen with parkin mutations and were indistinguishabl e from patients with sporadic PD. Conclusions: These findings confirm the r ecessive character of parkin mutations causing early-onset parkinsonism and the essential role of the ubiquitinlike region, highly conserved among spe cies, and in accordance with the proposed parkin function.