Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 822-833, 20 March 2008
doi:10.1016/j.ajhg.2008.01.015
Article
Mutations in the GIGYF2 (TNRC15) Gene at the PARK11 Locus in Familial Parkinson Disease
Corinne Lautier1, 2, 3, Stefano Goldwurm4, Alexandra Dürr2, 3, Barbara Giovannone1, William G. Tsiaras1, Gianni Pezzoli4, Alexis Brice2, 3 and Robert J. Smith1, 
, 
1 Division of Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 02903, USA
2 INSERM, U679 and Pierre and Marie Curie-Paris6 University, UMR S679, Pitié-Salpêtrière Hospital, Paris, 75013, France
3 AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, 75013, France
4 Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, 20126, Italy
Corresponding authorAbstract
The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.
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