ANXA1 with Anti-Inflammatory Properties Might Contribute to Parkinsonism.

We here describe the identification of a novel variant in the anti-inflammatory Annexin A1 protein likely to be the cause of disease in two siblings with autosomal recessive parkinsonism. The disease-segregating variant was ascertained through a combination of homozygosity mapping and whole genome sequencing and was shown to impair phagocytosis in zebrafish mutant embryos. The highly conserved variant, absent in healthy individuals and public SNP databases, affected a functional domain of the protein with neuroprotective properties. This study supports the hypothesis that damaged microglia might lead to impairments in the clearance of accumulated and aggregated proteins resulting in parkinsonism. ANN NEUROL 2021;90:319-323.

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

PTRHD1 (C2orf79) mutations lead to autosomal-recessive intellectual disability and parkinsonism.

INTRODUCTION: Atypical parkinsonism is a neurodegenerative disease that includes diverse neurological and psychiatric manifestations. OBJECTIVES: We aimed to identify the disease-cauisng mutations in a consanguineous family featuring intellectual disability and parkinsonism. METHODS: Full phenotypic characterization, followed by genome-wide single-nucleotide polymorphism genotyping and whole-genome sequencing, was carried out in all available family members. RESULTS: The chromosome, 2p23.3, was identified as the disease-associated locus, and a homozygous PTRHD1 mutation (c.157C>T) was then established as the disease-causing mutation. The pathogenicity of this PTRHD1 mutation was supported by its segregation with the disease status, its location in a functional domain of the encoding protein, as well as its absence in public databases and ethnicity-matched control chromosomes. CONCLUSION: Given the role of 2p23 locus in patients with intellectual disability and the previously reported PTRHD1 mutation (c.155G>A) in patients with parkinsonism and cognitive dysfunction, we concluded that the PTRHD1 mutation identified in this study is likely to be responsible for the phenotypic features of the family under consideration. © 2016 International Parkinson and Movement Disorder Society.

RIT2 Polymorphisms: Is There a Differential Association?

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.

SNAP-25 gene variations and attention-deficit hyperactivity disorder in Iranian population.

OBJECTIVES: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric condition of childhood characterized by persistent symptoms of hyperactivity, inattention, and impulsivity. The objective of this study was to investigate the association of synaptosomal-associated protein of 25 kDa (SNAP-25) gene variants with ADHD. METHODS: A case-control study with a total of 150 children with ADHD (mean age 9.61; range 6-16; gender ratio 105m/45f) and 150 normal children (mean age 10.02; range 6-16; gender ratio 98m/52f) was conducted. Genomic DNA was extracted from peripheral blood of all samples and SNPs rs78428954 and rs3746544 located in SNAP-25 gene were genotyped. RESULTS: Our analysis indicated that there is no significant association between none of studied variants in SNAP-25 and ADHD. DISCUSSION: To our knowledge, it is the first report of SNAP-25 genotyping in Iranian patients with ADHD. Further investigations with larger populations are needed in order to clarify the exact role of SNAP-25 variations in susceptibility to ADHD.

SIPA1L2, MIR4697, GCH1 and VPS13C loci and risk of Parkinson's diseases in Iranian population: A case-control study.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Prevalence of PD increases steadily with age. A recent meta-analysis of genome-wide association studies has identified six new loci to be linked with PD. Here we investigated the association of four of these new loci, SIPA1L2, MIR4697, GCH1 and VPS13C with PD in an Iranian population. Through a case-control study a total of 1800 subjects comprising 600 PD patients and 1200 unrelated healthy controls were recruited. Rs10797576, rs329648, rs11158026 and rs2414739 related to SIPA1L2, MIR4697, GCH1 and VPS13C loci respectively, were genotyped in all subjects. The difference of genotype and allele frequencies between case and control groups were investigated using chi-square test and logistic regression models with R software. Genotype and allele frequencies were significantly different in PD patients and control group for rs329648, rs11158026 and rs2414739 (p-value=0.018, 0.025, and 0.009 respectively for allele frequency differences). There was no difference in genotype nor allele frequencies between the two groups for rs10797576. We replicated the association of three new loci which are proposed for PD. More studies in other populations and also functional analysis are required to clear the role of these variants in PD.

Genetic Analysis of the ZNF512B, SLC41A1, and ALDH2 Polymorphisms in Parkinson's Disease in the Iranian Population.

AIMS: Parkinson's disease (PD) is one of the most common neurodegenerative disorders; its etiology includes both genetic and environmental factors and their interactions. The ZNF512B, SLC41A1, and ALDH2 genes have recently been identified as contributing to PD. In this study we investigated the association of alleles of these genes with PD in the Iranian population. METHODS: In a case-control study, rs2275294, rs11240569, and rs4767944, three single nucleotide polymorphisms in ZNF512B, SLC41A1, and ALDH2 genes, respectively, were genotyped in 490 PD patients and 490 controls. The genotype and allele frequencies were compared between the two groups using chi-square and logistic regression tests. RESULTS: A significant association between the rs11240569 polymorphism and a reduced risk of PD was found (p = 0.014, OR = 0.76, 95% CI: 0.60-0.94 for allele frequencies). We did not find any associations between PD and the rs2275294 and rs4767944 polymorphisms. CONCLUSION: The association of rs11240569 polymorphism in SLC41A1 gene with reduced risk of PD was replicated in our population.

c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness.

Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals.

The analysis of association between SNCA, HUSEYO and CSMD1 gene variants and Parkinson's disease in Iranian population.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Both genetic and environmental factors are involved in the etiology of the disease. Many studies have revealed the susceptibility genes and variations for PD which need further confirmation. Here we evaluated the association of variations in SNCA, HUSEYO and CSMD1 genes with PD. A case-control study was conducted with 489 PD patients and 489 healthy controls. DNA was extracted from peripheral blood of all subjects and rs356220 and rs11931074 in SNCA, rs2338971 in HUSEYO and rs12681349 in CSMD1 were genotyped using PCR-RFLP method. The genotypes and allele frequencies were significantly different between case and control groups for rs356220, rs11931074 and rs2338971 but not for rs12681349. We provided further evidence that rs356220 is associated with increased risk of PD supporting previous studies in Caucasian-based and Japanese populations. The association of rs11931074 with decreased risk of PD was also significant. This study revealed the first evidence of the association of rs2338971 with increased risk of PD in the Iranian population. Nevertheless, these findings need further validation via more replication studies.

A genetic variant in CAMKK2 gene is possibly associated with increased risk of bipolar disorder.

A recent large-scale study have reported that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene is highly associated with schizophrenia in European and Han Chinese populations. Increasing evidences show that schizophrenia and bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant with schizophrenia and bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500 schizophrenic patients, 500 bipolar patients and 500 normal controls and all were genotyped for the rs1063843 using a PCR-RFLP method. The allele frequency of rs1063843 was significantly different in both schizophrenia and bipolar patients comparing to control group. For the first time, we showed that rs1063843 is highly associated with bipolar disorder, although more replication studies are needed to confirm our findings. Our results also support the findings of previous studies suggesting a significant association between rs1063843 and schizophrenia.

Variation in the miRNA-433 binding site of FGF20 is a risk factor for Parkinson's disease in Iranian population.

DNA variations in the fibroblast growth factor 20 gene have been reported to be associated with Parkinson's disease (PD). The rs12720208, a functional SNP located in the 3'UTR region of the gene, was reported as a risk factor for PD. A number of studies, which tried to replicate the result in different populations, failed to detect any associations. In this study, we genotyped rs2720208 SNP in 520 PD patients and 520 healthy controls both from Iran. Significant differences were found in allele and genotype frequencies between patients and controls (p<0.0001 for both). Our results suggest that the rs12720208 polymorphism may be a risk factor for PD in Iranian population.