Mutations in the GIGYF2 (TNRC15) Gene at the PARK11 Locus in Familial Parkinson Disease

Abstract

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.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Another study of North American and Portuguese PD cases found two of these mutations, but only in healthy persons [256], and a study of primarily Italian cases found no mutations [257], casting doubt whether the GIGYF2 is a causative PD gene. In a large sample of US and Norwegian PD cases (in total 1,139 cases), one of the originally reported [172] mutations was identified in three US sporadic cases, but none of the other mutations were found [258].…”

“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

“…In 2008, 7 different heterozygous mutations were identified in the GIGYF2 gene (located at the linkage peak) in French and Italian PD cases with family history of PD [172]. However, when 96 PD cases from the original linkage study [176] were screened for GIGYF2 mutations, no mutations were found that consistently segregated with PD [254].…”

Maladies neurodégénératives et diabète

“…Cependant, le rôle spécifique de la protéine adaptatrice Grb10 dans le développement neurologique a déjà été suggéré par la découverte de mutations pathogènes dans le syndrome de Silver -Russell, qui associe un retard de croissance intra-utérin et un retard du développement psychomoteur ou du langage [13]. Notre étude du gène GIGYF2 par séquençage direct dans 249 cas familiaux (italiens et français) de la maladie de Parkinson et 227 témoins nous a permis d'identifier une mutation (faux-sens) du gène GIGYF2 chez 6 % des sujets atteints de maladie de Parkinson [14]. D'autre part, nous avons pu observer une importante variabilité de type insertion et délé-tion de codons glutamine (Glu).…”

The Shaking Palsy - Advances in Our Understanding of Parkinson's Disease

“…The discovery of genetic forms of PD, and the subsequent identification of the causative genes behind these cases, has provided us with important signposts towards research areas that we need to focus on in this disease. Recently, a putative thirteenth region of the genome has been identified, which is known to code for the protein TNRC15 (Lautier, 2008). It is likely that other such genes will be identified in the future.…”