Abstract Sepiapterin reductase ( SPR ) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a ...candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3′ untranslated region UTR) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I2 Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. We herein describe a family from southern Italy whose ...proband was a 49-year-old man presenting with ataxia with progressive gait disturbances, clumsiness and visual impairment. A molecular analysis identified 38 cytosine-adenine-guanine (CAG) repeat expansions within the SCA7 gene. Our study confirms the marked anticipation previously observed in SCA7 and extends the small number of patients studied thus far. In this family, the disease is most likely caused by a de novo expansion of a premutated intermediate allele carried by one parent.
•Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease.•The expansion of GGGGCC in C9orf72 is the major genetic causes of ALS and FTD.•The C9orf72 repeat was also rarely found in ...other disease, including MSA.•In this study was reported an analysis of C9orf72 in 100 MSA italians patients.•We detect the C9orf72 repeat in 2 MSA patients and the intermediate repeat in four.
Exanucleotide expansions in C9orf72 gene have been described as potential risk factor in some patients with Multiple system atrophy (MSA) and other forms of atypical parkinsonism. The goal of our study was to extend the knowledge on the involvement of C9orf72 in MSA studying a cohort of 100 patients from Italy. We identified 2 heterozygous patients in the pathological range (> 30 repeats) and 4 heterozygous patients for expansions in the premutation range (20 -30 repeats). Our findings strengthen the previously hypothesized role for this gene as a risk factor for MSA and raise the possibility of a more complex and still unknown involvement of this gene in the heterogeneity of MSA.
Recently, a novel pathogenic variant in Annexin A1 protein (c.4G > A, p.Ala2Thr) has been identified in an Iranian consanguineous family with autosomal recessive parkinsonism. The deficiencies of ...ANXA1 could lead to extracellular SNCA accumulation, defects in intracellular signaling pathways and synaptic plasticity causing parkinsonism. The aim of this study was to identify rare ANXA1 variants in 95 early-onset PD patients from South Italy. Sequencing analysis of ANXA1 gene revealed only 2 synonymous variants in PD patients (rs1050305, rs149033255). Therefore, we conclude that the recently published ANXA1 mutation is not a common cause of EOPD in Southern Italy.
•We screened 250 PD and 100 MSA for the ATP13A2 gene.•We identified a missense (c.3059A>G) in heterozygous in a MSA patient.•The relationship between ATP13A2 and MSA is still unknown, further studies ...are needed to clarify the functional role of this genetic risk factor.
Summary
Heterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or ...familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.
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