Mutations In PLA2G6 Gene Research Articles

Identification and bioinformatics analysis of a novel mutation in PLA2G6 gene in a patient with neurodegenerative disorder

PLA2G6-associated neurodegeneration disorders are a group of conditions that result from mutations in the PLA2G6 gene. These disorders can cause a range of symptoms affecting the brain and nervous system, such as movement problems, cognitive decline, and vision loss. In this case, Whole Exome Sequencing (WES) was conducted on a 9-year-old boy born to consanguineous parents, who have an increased risk of passing on recessive genetic disorders. Although the boy did not exhibit any clinical symptoms until he was seven months old, his condition deteriorated severely by the age of two, rendering him unable to sit or move around, and he did not develop the ability to speak. DNAs were extracted from the blood samples of the proband (the 9-year-old boy) and his parents. The proband's DNA was sequenced using WES to identify potential disease-causing mutations. To confirm the WES findings, PCR-Sanger sequencing analysis was performed on the DNAs obtained from the proband (the 9-year-old boy) and his parents. The effect of the mutation on the protein structure was studied using the I-TASSER web-tool, which uses computational methods to predict protein structure and function based on amino acid sequences.The analysis of WES data revealed a homozygous dinucleotide TG insertion at position c.1362–1363 in exon 10 of the PLA2G6 gene (NC_000022.11(NM_003560.4):c.1362_1363insTG). This insertion introduced a premature stop codon at position 455 (p.Met455Ter) in the protein sequence. The validation of the WES results using PCR-Sanger sequencing confirmed the presence of the mutation in the proband and revealed that both parents were carriers of the mutation. The premature stop codon, located 65 nucleotides before the exon-junction complex, is likely to be detected by the nonsense-mediated mRNA decay (NMD) pathway, leading to the degradation of the mRNA. The use of the I-TASSER web-tool further supported the findings by demonstrating significant structural and functional changes in the mutant protein. Observing a very severe phenotype in our case supports the idea that the mutation was highly deleterious.

Spectrum of Neurodegeneration with Brain Iron Accumulation with PLA2G6 Variation: A Report of Three Cases from Two Families

AbstractNeurodegeneration with brain iron accumulation consists of disorders characterized by progressive neuronal degeneration, cognitive decline, brain iron accumulation in extrapyramidal system, dentate nucleus, and gray and white matters boundary. We present a case series of PLA2G6-associated neurodegeneration (PLAN), with definite PLA2G6 gene mutations in two cases and suspected in one case. Diagnosis was based on clinical presentations, brain magnetic resonance imaging (MRI) findings, and detection of PLA2G6 mutations. Case 1: An 8-year-old boy presented with weakness of lower limbs, subnormal intelligence, scanning speech, spasticity, dysdiadochokinesia, pendular knee jerk, and extensor plantar reflex. MRI of the brain showed diffuse cerebellar atrophy and white matter T2 hyperintensity with iron deposition in bilateral globus pallidi. Case 2: Elder sister of Case 1, who developed ataxia at the age of 6 years and became bedridden at 14 years. She had nocturnal enuresis, seizures, cervical dystonia, dysphagia, and died at 23 years of age. MRI showed cerebral and cerebellar atrophies and iron deposition in basal ganglia and substantia nigra. Case 3 had infantile onset with quadriparesis, optic atrophy, developmental delay, cerebral and cerebellar atrophies, and brain iron accumulation in basal ganglia. Case 1 revealed two heterozygous mutations of PLA2G6 gene in exons 16 (c.2264G > A, p. Arg755Gln) and 12 (c.1637G > A, p. Arg546Gln), classified as likely pathogenic. Elder sister (Case 2) could not be tested for this mutation. Case 3 showed homozygous silent splice site point variation in exon 7 (c.1077 G > A; p. Ser 359 Ser) of PLA2G6 gene. Thus, in patients presenting with neurodegeneration and imaging findings of brain iron accumulation, diagnosis can be established by PLA2G6 gene mutation analysis.

NBIA Syndromes: A Step Forward from the Previous Knowledge.

A disturbed iron metabolism may damage brain and trigger disorders known as neurodegeneration with brain iron accumulation (NBIA). NBIAs are rare, inherited disorders in which responsible mutations affect the function of proteins that participate in tissue iron homeostasis. Accumulated iron, which may be recognized as a low signal intensity on T2-weighted MRI images, oftentimes points to a diagnosis. Recent genetic discoveries confirm that NBIA is not a homogenous group of diseases. Fifteen different NBIAs have been described to date; among these, autosomal recessive inheritance was reported in 13, and autosmal dominant and X-linked dominant inheritance in one disease, respectively. Among NBIAs, the most common is pantothenate kinase-associated neurodegeneration (PKAN-NBIA 1) (30%-50% of all NBIA cases), that occurrs as a consequence of the autosomal recessive mutation in PANK2 gene, followed by phospholipase 2-associated neurodegeneration (PLAN, NBIA 2), due to mutation in PLA2G6 gene, and mitochondrial membrane protein-associated neurodegeneration (MPAN) with the underlying C19orf12 mutation [Table 1]. NBIAs are characterized by complex motor presentations from early-onset degeneration and premature fatality to adult-onset parkinsonism and dystonia. Epileptic seizures, pyramidal signs, visual disorders, and cognitive deterioration can develop. NBIAs are often refractory to therapeutical strategies, although certain interventions may provide significant symptomatic relief in selected patients. In this review, we discuss the expanding clinical spectrum of these complex and rare syndromes, their genetic and imaging features, and potential therapeutical targets and strategies.

Generation of induced pluripotent stem cells from a young-onset Parkinson's disease patient carrying the compound heterozygous PLA2G6 p.D331Y/p.M358IfsX mutations.

Mutations in PLA2G6 gene cause PLA2G6-associated neurodegeneration, including recessive familial type 14 of Parkinson's disease (PARK14). Previously, we identified PARK14 patients with compound heterozygous c.991G > T/c.1077G > A (p.D331Y/p.M358IfsX) mutations. The c.1077G > A mutation led to a four base-pairs deletion and frameshift mutation (p.M358IfsX) of PLA2G6 mRNA. We established induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient with compound heterozygous c.991G > T/c.1077G > A (p.D331Y/ p.M358IfsX) mutations by using Sendai-virus delivery system. The iPSCs exhibited pluripotency and in vivo differentiation potential. The iPSCs can be used for studying the molecular pathogenic mechanism of PARK14.

Identification of a novel mutation in PLA2G6 gene and phenotypic heterogeneity analysis of PLA2G6-related neurodegeneration

IntroductionThis study reports a novel mutation site of the phospholipase A2 group VI (PLA2G6) gene, and analyzes the information of 67 previously published cases to elucidate PLA2G6 phenotype-genotype variations. MethodsWe collected clinical data and examined gene mutation sites from one Chinese patient with adult-onset ataxia and her family. Next-generation sequencing (NGS) and Sanger sequencing were used to verify possible mutations. PolyPhen-2, SIFT, and MutationTaster were used to predict their pathogenicity. For analyzing the distribution frequency of the mutation, 597 healthy controls were recruited. We also analyzed the clinical and genetic information of 67 cases from 23 studies in Pubmed database. ResultsA novel compound heterozygous mutation of the PLA2G6 gene, c.1648delC and c.991G > T, was found in the Chinese patient, and classified as pathogenic. The c.1648delC variation was absent in ExAC, 1000G, dbSNP databases and the 597 healthy controls. Of the 67 cases, 29 presented ataxia. The signs of cerebellar atrophy appeared in the MRIs of most patients, while signs of iron accumulation were absent in older-aged patients with a compound heterozygous mutation. Thirty-eight patients showed no ataxia. A negative or mild extrapyramidal symptom accompanied by a low age, a homogenous mutation, while moderate or severe extrapyramidal symptoms were associated with an old age and a compound heterozygous mutation. ConclusionA novel compound heterozygous mutation of the PLA2G6 gene, c.1648delC and c.991G > T, is associated with adult onset ataxia. Phenotype-genotype variations of PLA2G6 are predicted to be caused by the loss of protein or enzyme activity of phospholipase-2.

Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family

BackgroundInfantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent.Case presentationTwo Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members.ConclusionThis variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients’ phenotype). Therefore this variant can be currently annotated as “pathogenic”. This is the first study to report mutations in PLA2G6 gene in patients from Sudan.

Neurodegeneration with brain iron accumulation 2A: Report of four independent cases

Neurodegeneration with brain iron accumulation-2A (NBIA2A, also called infantile neuroaxonal dystrophy) is an autosomal recessive disorder of the central nervous system (CNS) caused by mutations in PLA2G6 gene. The characteristic features of NBIA2A are progressive course of mental and motor regression, cerebellar ataxia, hypotonia, spastic tetraplegia, hyperreflexia and visual defects. In the present study we report four independent cases of NBIA2A whose genetic defects have been identified through whole exome sequencing. Three novel mutations and a previously reported mutation have been detected in PLA2G6 gene in these patients. Identification of these mutations facilitated effective genetic counseling and prenatal diagnosis in the families.

A new PLA2G6 mutation in a family with infantile neuroaxonal dystrophy

Phospholipase A2-associated neurodegeneration (PLAN), a syndrome of Neurodegeneration with Brain Iron Accumulation (NBIA), is an autosomal recessive disorder caused by mutations in PLA2G6 gene. This gene encodes a calcium-independent group VI phospholipase A2 (iPLA-VI) critical in cell membrane homeostasis.PLAN syndrome encompasses a group of phenotypes with a different age of onset: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy of childhood-onset (atypical NAD) and adult-onset PLA2G6-related dystonia-parkinsonism (PARK14).INAD is a severe progressive psychomotor disorder characterized by the presence of axonal spheroids throughout the central and peripheral nervous system. Here we report clinical, genetic and histopathological findings of an INAD consanguineous-family from Senegal. Sanger sequencing analysis revealed a new homozygous PLA2G6-mutation in the proband (c.1483C>T) and the co-segregation of the mutation in this family.Electron microscopy on skin biopsy showed degenerated axons confirming the phenotype.This study contributes to enrich the landscape of PLA2G6-associated INAD mutations and enforce the genotype-phenotype correlation.

Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports

BackgroundNeurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. The purpose of this study was to investigate disease-causing mutations in two patients with distinct NBIA disorders.Case presentationWhole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. In addition, our study revealed a novel missense mutation in PLA2G6 gene (c.3G > T:p.M1I) in one and half-year-old boy with muscle weakness and neurodevelopmental regression (speech, motor and cognition). The novel mutations were also confirmed by Sanger sequencing in the proband and their parents.ConclusionsCurrent study uncovered two rare novel mutations in PANK2 and PLA2G6 genes in patients with NBIA disorder and such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these types of disorders.

PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia.

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

Ultrastructural features of canine neuroaxonal dystrophy in a Papillon dog.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by severe axonal swelling (spheroids) throughout the nervous system. In dogs, NAD has been reported in several breeds and a missense mutation in PLA2G6 gene has recently been identified in the Papillon dog NAD. Here we performed ultrastructural analysis to clarify the detailed ultrastructural features of the Papillon dog NAD. Dystrophic axons consisted of accumulation of filamentous materials, tubulovesicular structures, and swollen edematous mitochondria with degenerated inner membranes were often observed in the central nervous system. At axonal terminals, degeneration of presynaptic membrane was also detected. As reported in Pla2g6 knockout mice, mitochondrial and presynaptic degeneration may be related with the pathogenesis of NAD in Papillon dogs.

A new missense mutation in PLA2G6 gene among a family with infantile neuroaxonal dystrophy INAD

We report a family with two siblings having features of infantile neuroaxonal dystrophy (INAD), with first degree consanguineous parents. Rapid progressive loss of developing milestones (started from 18months) and early infantile death of both siblings occurred. Brain magnetic resonance imaging (MRI) revealed severe rapidly progressive cerebellar atrophy initially reported as early as 18months, with the younger brother suffered generalized tonic clonic seizures.Next generation sequencing revealed a new mutation in PLA2G6 gene (c.319 del C, p. Leu107 Cyst), resulting in a premature stop codon with shift in the reading frame of resulting protein. ConclusionEarly onset loss of developmental milestones with cerebellar atrophy and other described clinical findings ultimately warrant PLA2G6 gene sequencing. Here we report c.319 del. C of PLA2G6 detected by next generation sequencing to be responsible for severe early infantile neuroaxonal dystrophy with early infantile death. We conclude that various PLA2G6 gene sites sequencing need further investigation in INAD in line with clinical correlation. Also INAD seems to be an unrecognized disorder that needs more categorization for proper diagnosis and genetic counselling.

Novel Mutation in PLA2G6 Gene in a Patient with Infantile Neuroaxonal Dystrophy

AbstractInfantile neuroaxonal dystrophy (INAD) is an autosomal recessive disorder that causes psychomotor regression. Clinicopathological features include truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, cerebellar ataxia, bulbar dysfunction, and cerebellar atrophy. INAD is associated with a variety of mutations in the PLA2G6 gene that encodes the group VI calcium-independent phospholipase A2 protein which is important in cell membrane homeostasis. Defects in this protein cause axonal dystrophy. We report a 2-year-old boy with INAD who was found to have a novel deletion c.1019_1025del7 leading to a frame shift in the PLA2G6 gene. We suggest that this change may be an addition to the array of mutations causing INAD.

Monozygotic twins with infantile neuroaxonal dystrophy: A case report and literature review.

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disease with early onset. PLA2G6 gene mutations have been identified in the majority individuals with INAD. In future, molecular diagnosis of INAD will replace the invasive biopsies used previously. In the present report, monozygotic male twins with INAD were referred The Children's Hospital (Zhejiang University School of Medicine, Zhejiang, China) at fifteen months old for delayed development. The older brother was found to have developmental stagnation when he was 6 months old. The patient could not stand securely without support, and had poor eye tracking and listening ability. Magnetic resonance imaging (MRI) of the patient's brain revealed cerebellar atrophy and electromyography identified signs of peripheral neuropathy. The younger brother displayed similar clinical features and findings. Two different phospholipase A2 group VI (PLA2G6; 22q13.1) gene mutations were detected in the twins by DNA sequencing. The results of the present study indicate that neurogenetic disease should be considered when child patients present with idiopathic developmental stagnation, particularly when similar cases have appeared in the same family. In addition, INAD should be considered as a possible diagnosis when the patient has developmental delay of the central and peripheral nerves. In the future, molecular genetic testing will be the primary method of INAD diagnosis, enabling better prevention of this genetic disease.

Identification of a novel mutation in PLA2G6 gene in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy

PurposeFamilial cortical myoclonic tremor with epilepsy (FCMTE) is an epileptic syndrome with autosomal dominant inheritance, of which four genetic subtypes (FCMTE1-4) have been reported. In the present study, we described the clinical and neurophysiologic features of a newly diagnosed Chinese FCMTE family, and investigated the genetic cause for this disease. MethodsClinical information was obtained from affected and normal individuals of an FCMTE family comprising 41 members. Electroencephalographies were analyzed in five of six affected members (including the proband). Brain magnetic resonance imaging, somatosensory evoked potential with C-reflex analysis and magnetoencephalography was performed in the proband. Genomic DNA of three affected and two unaffected individuals was analyzed to detect the genetic mutations by using whole-exome sequencing. ResultsThe inheritance pattern of the pedigree was autosomal dominant. A novel missense mutation c.475C>T (p.Ala159Thr) of PLA2G6 were identified in this family. The mutated locus is highly conserved among other species. The mutation is predicted to have a functional impact, and completely co-segregated with the phenotype. ConclusionThis study identifies a novel PLA2G6 mutation that is the possible genetic cause of FCMTE in this family. This mutation and associated clinical features expand the spectrum and phenotypes of PLA2G6-related disorders including neurodegenerative diseases.

In the neurodegenerative disease INAD, infantile neuroaxonal dystrophy, glutamate‐ and ATP‐induced Ca2+ signaling is disturbed in neurons and astrocytes, with mitochondrial dysfunction

About 85% of cases of INAD (infantile neuroaxonal dystrophy, OMIM #256600), an autosom al recessive inherited degenerative disease with early onset can be associated with mutations of the PLA2G6 gene . Ca2+‐independent phospholipase A2 (VIA iPLA2) is encoded in PLA2G6 . However, connections of these mutations to disease are unclear. For the mainly phospholipid metabolizing VIA iPLA2 also so‐called non‐canonical functions were discussed and reported. These are regulation of store‐regulated Ca2+ entry in cells and change in mitochondrial Ca2+ homeostasis. In this study, we investigate glutamate‐evoked Ca2+ signals in neurons and astrocytes in co‐culture from three INAD mouse models with Pla2g6 gene mutations. The strain‐1 has a hypomorphic Pla2g6 allele with reduced transcript levels (5% of wild type), the strain‐2 has knocked‐out Pla2g6, and strain‐3 has a Pla2g6 point mutation with the VIA iPLA2 inactive. It is shown that homozygous offspring from all strains develop pathology similar to that observed in INAD patients. We demonstrate in our present study a strongly reduced glutamate‐induced Ca2+ response in mutants in astrocytes compared to control cells. When we elucidate the mechanism we find that reduced Ca2+ responses are due to about 2‐fold‐reduced Glu‐induced capacitative Ca2+ entry in astrocytes in all three mouse strains. This effect is based on the lack in VIA iPLA2 activity since we could mimic the decrease by pharmacologically inhibiting iPLA2 with the compound S‐BEL enantiomer. On the contrary, in neurons the Pla2g6 mutation completely disrupted the influence of mitochondrial Ca2+ uptake on the extracellular Glu‐induced Ca2+ influx . We see it in neurons treated with Ru360, a blocker of mitochondrial Ca2+ uniporter or treated with rotenone. The dependency of Glu‐induced Ca2+ influx on mitochondrial Ca2+ uptake was wiped out in neurons with Pla2g6 mutation, whereas a strong reduction was seen in wild‐type cells. Thus, all INAD models have comparable changes, but they are different for astrocytes and neurons, respectively, in Glu‐induced Ca2+ signaling. These modifications in Ca2+ signaling in cells with mutated Pla2g6 are critical for adequate neuron‐astrocyte communication. Thus our data help to understand molecular mechanisms of INAD pathology.Support or Funding InformationDeutsche Forschungsgemeinschaft (Re 563‐22‐1)

Correction: New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

There were errors in the Funding section. The correct funding information is as follows: MAS and co-authors are thankful to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, for supporting the work through the research group project number RGP-VPP-301. RC was supported by the Gebert Ruf Foundation (grant number GRS-046/09). GS was supported by the French National Agency for Research(ANR), Association Contre les Syndromes Cerebelleux, France, The Verum Foundation, the European Union (Omics call, Neuromics), The Fondation Roger de Spoelberch and the program Investissements d'avenir ANR-10-IAIHU-06 (to the Brain and Spine Institute). HA was supported by Association Francaise contre les Myopathies (AFM), France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients’ muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Analysis of PLA2G6 gene mutation in sporadic early-onset parkinsonism patients from Chinese population

Recent studies have shown that PLA2G6 is a causative gene for PARK14-linked autosomal recessive early-onset complicated dystonia-parkinsonism, early-onset parkinsonism with frontotemporal dementia and autosomal recessive early-onset Parkinsonism without added complicated clinical features. In order to investigate the characteristics of PLA2G6 gene mutations in Chinese sporadic early-onset parkinsonism (EOP) patients, we performed polymerase chain reaction and DNA direct sequencing on a cohort of sporadic EOP patients from Chinese population. In this study, we found a novel heterozygous varient (p.G679V). Bioinformatics demonstrates that p.G679V exhibits highly conserved residues across species, which hints it might be a pathogenic mutation. Our result indicated that PLA2G6 mutations might not be a main cause of Chinese sporadic EOP.

PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort

Mutations in the PLA2G6 gene at the PARK14 locus have been reported in complicated parkinsonism. To assess the prevalence of and phenotypes associated with PLA2G6 gene mutations, we screened PLA2G6 mutations in a cohort of patients with autosomal recessive early-onset parkinsonism (AREP). We selected 12 families with AREP in which the Parkin, PINK1, DJ-1, ATP13A2, and FBXO7 gene mutations had been previously excluded. All patients came from the mainland of China. The entire PLA2G6 coding region and exon-intron boundaries were sequenced from genomic DNA templates. We then performed PET studies on individuals in the pedigree with a homozygous PLA2G6 mutation, and investigated the enzyme activity level of the mutation. A homozygous missense mutation, c.G991T (p.D331Y), was identified in an autosomal recessive case. A younger sister of the p.D331Y-carrying patient was also homozygous for the mutation, but with no extrapyramidal symptoms. A PET study showed a substantial reduction in dopamine transporter (DAT) binding in the p.D331Y patient, and a slight reduction in DAT binding in his sister. In vitro, we experimentally demonstrate that the D331Y mutation caused an approximately 70%reduction in enzyme activity. We have confirmed that the PLA2G6 gene allocated PARK14 locus and is associated with AREP.