New mutation (R42P) 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 first-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.


METHODS
Three brothers were examined clinically at several stages of the disease. Single-strand conformational polymorphism analysis was done on the parkin gene of 32 members of the family. Samples showing mobility shifts were considered for mutation analysis.


RESULTS
Direct DNA sequencing revealed a novel homozygous amino acid substitution, Arg42Pro, in all three patients compared with a control DNA sample. The mutation occurred in the ubiquitinlike domain at the N-terminal of the protein. The patients did not display the clinical hallmarks previously seen with parkin mutations and were indistinguishable from patients with sporadic PD.


CONCLUSIONS
These findings confirm the recessive character of parkin mutations causing early-onset parkinsonism and the essential role of the ubiquitinlike region, highly conserved among species, and in accordance with the proposed parkin function.
Biology of Neurodegenerative Disorders Laboratory, Istituto di Ricerche, Farmacologiche "Mario Negri", Milan, Italy.
L
L
Terreni
E
E
Calabrese
A M
AM
Calella
G
G
Forloni
C
C
Mariani
D004247:DNA / Q000032:analysis; D005260:Female; D006801:Humans; D007558:Italy; D008025:Ligases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000235:genetics*
D014452:Ubiquitins; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases