Coro Paisán-Ruiz

Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease

Parkinsons disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.

Genome-wide association study reveals genetic risk underlying Parkinson's disease

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinsons disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinsons disease. We measured the frequency of a novel mutation (Gly2019 ser) in familial Parkinsons disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinsons disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinsons disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinsons disease.

Characterization of PLA2G6 as a locus for dystonia-parkinsonism.

Although many recessive loci causing parkinsonism dystonia have been identified, these do not explain all cases of the disorder.

The genetics of Parkinson's syndromes: a critical review

Genetic analysis has identified many loci designated as PARK loci (OMIM #168600). Many of these loci do not refer to idiopathic Parkinsons disease which is characterized by Lewy body pathology, but rather to clinical parkinsonisms. In this review, besides reviewing the genetic of the disorder, we argue that this designation is misleading and that if we seek to understand the pathogenesis, we should study the genetics of Lewy body diseases: these include not only idiopathic Parkinsons disease, but also such disparate syndromes as Hallevorden-Spatz disease and Niemann-Pick Type C.

Early-onset L-dopa-responsive Parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and Spatacsin mutations

Seven autosomal recessive genes associated with juvenile and young‐onset Levodopa‐responsive parkinsonism have been identified. Mutations in PRKN, DJ‐1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor‐Rakeb syndrome has additional signs, which distinguish it clearly from Parkinsons disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden‐Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor‐Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido‐pyramidal syndrome.

Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA).

Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult‐onset parkinsonism‐dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA.

DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA

BACKGROUND Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved. METHODS We identified two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. We did autozygosity mapping and candidate gene sequencing in these families. FINDINGS High-density genome-wide SNP genotyping revealed a disease-segregating region containing 277 homozygous markers identical by state across all affected members from both families. This novel disease locus, designated DYT16, covers 1.2 Mb at chromosome 2q31.2. The crucial interval contains 11 genes or predicted transcripts. Sequence analysis of every exon of all of these transcripts revealed a single disease-segregating mutation, c.665C>T (P222L), in the stress-response gene PRKRA, which encodes the protein kinase, interferon-inducible double-stranded RNA-dependent activator. INTERPRETATION We describe a mutation within the gene PRKRA that segregates with a novel, autosomal recessive, dystonia parkinsonism syndrome. These patients have progressive, generalised, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia and, in some cases, parkinsonian features, and do not respond to levodopa therapy.

The Sac1 Domain of SYNJ1 Identified Mutated in a Family with Early-Onset Progressive Parkinsonism with Generalized Seizures

This study aimed to elucidate the genetic causes underlying early‐onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole‐exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2‐terminal Sac1‐like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease‐segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.

Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations

The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.