Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism.

Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis.

Olfactory heterogeneity in LRRK2 related Parkinsonism.

LRRK2 mutations can cause familial and sporadic Parkinson's disease (PD) with Lewy-body pathology at post-mortem. Studies of olfaction in LRRK2 are sparse and incongruent. We applied a previously validated translation of the 16 item smell identification test from Sniffin' Sticks (SS-16) to 14 parkinsonian carriers of heterozygous G2019S LRRK2 mutation and compared with 106 PD patients and 118 healthy controls. The mean SS-16 score in LRRK2 was higher than in PD (p < 0.001, 95% CI for ß = -4.7 to -1.7) and lower than in controls (p = 0.007, 95% CI for ß = +0.6 to +3.6). In the LRRK2 group, subjects with low scores had significantly more dyskinesia. They also had younger age of onset, longer disease duration, and reported less frequently a family history of PD, but none of these other differences reached significance. Odor identification is diminished in LRRK2 parkinsonism but not to the same extent as in idiopathic PD.

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.

Mutations in the LRRK2 gene have been identified in families with autosomal dominant parkinsonism. We amplified and sequenced the coding region of LRRK2 from genomic DNA by PCR, and identified a heterozygous mutation (Gly2019 ser) present in four of 61 (6.6%) unrelated families with Parkinson's disease and autosomal dominant inheritance. The families originated from Italy, Portugal, and Brazil, indicating the presence of the mutation in different populations. The associated phenotype was broad, including early and late disease onset. These findings confirm the association of LRRK2 with neurodegeneration, and identify a common mutation associated with dominantly inherited Parkinson's disease.

GIGYF2 mutations are not a frequent cause of familial Parkinson's disease.

Mutations in the Grb10-interacting GYF protein 2 (GIGYF2) gene, within the PARK11 locus, have been nominated as a cause of Parkinson's disease in Italian and French populations. By sequencing the whole GIGYF2 coding region in forty-six probands (thirty-seven Italians) with familial Parkinson's disease compatible with an autosomal dominant inheritance, we identified no mutations. Our data add to a growing body of evidence suggesting that GIGYF2 mutations are not a frequent cause of PD.

Early-onset Parkinson's disease caused by a novel parkin mutation in a genetic isolate from north-eastern Brazil.

We describe clinical and molecular findings in a genetic isolate from north-eastern Brazil with early-onset Parkinson's disease (PD) and a novel mutation in the parkin gene. Genealogical studies could connect 255 individuals, of whom 15 had PD. Geographic isolation and multiple consanguineous marriages initially suggested an autosomal recessive inheritance for PD in these patients. The available individuals were personally examined, and DNA was obtained from 26 members: ten early-onset PD patients, one case with likely neuroleptic-induced parkinsonism and 15 unaffected relatives. The average age at onset of PD symptoms was 30.8 years (range 12-46). Haplotype analysis revealed homozygosity in the PD patients for markers across the PARK2 locus. Genomic sequencing identified a novel homozygous splice-site parkin mutation (IVS1 + 1G/T), which completely co-segregated with the early-onset PD phenotype. cDNA analysis confirmed the total loss of parkin transcript in homozygous mutation carriers, delineating this as a loss-of-function mutation. The case with neuroleptic-induced parkinsonism and 13 of 15 healthy relatives were heterozygous carriers of the mutation. The absence of PD in heterozygous carriers indicates a genuinely recessive nature of this mutation, suggesting that parkin haploinsufficiency is not a relevant risk factor for early- or late-onset PD. However, parkin haploinsufficiency could facilitate the emergence of neuroleptic-induced parkinsonism. The cluster reported here, which to our knowledge is the largest described to date with early-onset PD and parkin mutations, also offers a unique opportunity for the search of modifiers of the parkin-related disease.