ABSTRACT
Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.
Subject(s)
Congenital Disorders of Glycosylation/genetics , Genes, Dominant , Hexosyltransferases/genetics , Membrane Proteins/genetics , Musculoskeletal Diseases/genetics , Nervous System Diseases/genetics , Adolescent , Adult , Amino Acid Sequence , Catalytic Domain , Child, Preschool , Female , Heterozygote , Hexosyltransferases/chemistry , Humans , Male , Membrane Proteins/chemistry , Middle Aged , Pedigree , Sequence Homology, Amino AcidABSTRACT
Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts.
Subject(s)
Congenital Disorders of Glycosylation , Congenital Disorders of Glycosylation/diagnosis , Congenital Disorders of Glycosylation/genetics , Glycomics , Glycosylation , Humans , Mannose , Mannosyltransferases/genetics , N-Acetylglucosaminyltransferases , Oligosaccharides , Polysaccharides/geneticsABSTRACT
Lysosomal storage diseases (LSDs) are rare to extremely rare monogenic disorders. Their incidence, however, has probably been underestimated owing to their complex clinical manifestations. Sialidosis is a prototypical LSD inherited as an autosomal recessive trait and caused by mutations in the NEU1 gene that result in a deficiency of alpha-N-acetyl neuraminidase 1 (NEU1). Two basic forms of this disease, type I and type II, are known. The dysmorphic type II form features LSD symptoms including congenital hydrops, dysmorphogenetic traits, hepato-splenomegaly and severe intellectual disability. The diagnosis is more challenging in the normosomatic type I forms, whose clinical findings at onset include ocular defects, ataxia and generalized myoclonus. Here we report the clinical, biochemical and molecular analysis of five patients with sialidosis type I. Two patients presented novel NEU1 mutations. One of these patients was compound heterozygous for two novel NEU1 missense mutations: c.530A>T (p.Asp177Val) and c.1010A>G (p.His337Arg), whereas a second patient was compound heterozygous for a known mutation and a novel c.839G>A (p.Arg280Gln) mutation. We discuss the impact of these new mutations on the structural properties of NEU1. We also review available clinical reports of patients with sialidosis type I, with the aim of identifying the most frequent initial clinical manifestations and achieving more focused diagnoses.
Subject(s)
Ataxia/diagnosis , Mucolipidoses/diagnosis , Mucolipidoses/genetics , Myoclonus/diagnosis , Neuraminidase/genetics , Adolescent , Adult , Child , Diagnosis, Differential , Female , Humans , Lysosomes/pathology , Mutation, Missense , Phenotype , Young AdultABSTRACT
BACKGROUND: A minimally invasive test for early detection and monitoring of Parkinson's disease (PD) is a highly unmet need for drug development and planning of patient care. Blood plasma represents an attractive source of biomarkers. MicroRNAs (miRNAs) are conserved noncoding RNA molecules that serve as posttranscriptional regulators of gene expression. As opposed to ubiquitously expressed miRNAs that control house-keeping processes, brain-enriched miRNAs regulate diverse aspects of neuron development and function. These include neuron-subtype specification, axonal growth, dendritic morphogenesis, and spine density. Backed by a large number of studies, we now know that the differential expression of neuron-enriched miRNAs leads to brain dysfunction. OBJECTIVES: The aim was to identify subsets of brain-enriched miRNAs with diagnostic potential for familial and idiopathic PD as well as specify the molecular pathways deregulated in PD. METHODS: Initially, brain-enriched miRNAs were selected based on literature review and validation studies in human tissues. Subsequently, real-time reverse transcription polymerase chain reaction was performed in the plasma of 100 healthy controls and 99 idiopathic and 53 genetic (26 alpha-synucleinA53T and 27 glucocerebrosidase) patients. Statistical and bioinformatics analyses were carried out to pinpoint the diagnostic biomarkers and deregulated pathways, respectively. RESULTS: An explicit molecular fingerprint for each of the 3 PD cohorts was generated. Although the idiopathic PD fingerprint was different from that of genetic PD, the molecular pathways deregulated converged between all PD subtypes. CONCLUSIONS: The study provides a group of brain-enriched miRNAs that may be used for the detection and differentiation of PD subtypes. It has also identified the molecular pathways deregulated in PD. © 2019 International Parkinson and Movement Disorder Society.
Subject(s)
Circulating MicroRNA , MicroRNAs , Parkinson Disease , Brain/metabolism , Humans , MicroRNAs/genetics , Parkinson Disease/diagnosis , Parkinson Disease/genetics , alpha-Synuclein/metabolismABSTRACT
Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.
Subject(s)
Alkaline Phosphatase/metabolism , Cholesterol/metabolism , Golgi Apparatus/genetics , Homeostasis , Membrane Proteins/deficiency , Transaminases/metabolism , Adult , Amino Acid Sequence , Ceruloplasmin/metabolism , Endoplasmic Reticulum/metabolism , Exome , Fibroblasts/metabolism , Genotype , Glycosylation , Golgi Apparatus/metabolism , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Molecular Sequence Data , Mutation , Phenotype , Young AdultABSTRACT
The congenital disorders of glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N-glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue-restricted clinical symptoms in the various defects in dolichol-phosphate-mannose (DPM) synthesis remains unexplained. To deepen our understanding of the tissue-specific characteristics of defects in the DPM synthesis pathway, we investigated N-glycosylation and O-mannosylation in skeletal muscle of three DPM3-CDG patients presenting with muscle dystrophy and hypo-N-glycosylation of serum transferrin in only two of them. In the three patients, O-mannosylation of alpha-dystroglycan (αDG) was strongly reduced and western blot analysis of beta-dystroglycan (ßDG) N-glycosylation revealed a consistent lack of one N-glycan in skeletal muscle. Recently, defective N-glycosylation of ßDG has been reported in patients with mutations in guanosine-diphosphate-mannose pyrophosphorylase B (GMPPB). Thus, we suggest that aberrant O-glycosylation of αDG and N-glycosylation of ßDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo-N-glycosylation of ßDG or other skeletal muscle proteins contribute to the phenotype of patients with defects in DPM synthesis. Our findings contribute to our understanding of the tissue-restricted phenotype of DPM3-CDG and other defects in the DPM synthesis pathway.
Subject(s)
Congenital Disorders of Glycosylation/diagnosis , Congenital Disorders of Glycosylation/genetics , Mannosyltransferases/genetics , Membrane Proteins/genetics , Muscular Dystrophies/diagnosis , Adult , Biopsy , Child , Dystroglycans/genetics , Dystroglycans/metabolism , Female , Glycosylation , Humans , Male , Mannosyltransferases/metabolism , Membrane Proteins/metabolism , Middle Aged , Muscle, Skeletal/pathology , Mutation , PhenotypeSubject(s)
Parkinson Disease , Humans , alpha-Synuclein/genetics , Apolipoproteins E/genetics , Cognition , Genotype , Parkinson Disease/geneticsABSTRACT
BACKGROUND: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse. METHODS: The study population consisted of two Greek NPC patients and their extended pedigree. Patients' clinical, biochemical, molecular profiles and the possible correlations are presented. Genotyping was performed by direct sequencing. Mutations' origin was investigated through selected exonic NPC1 polymorphisms encountered more frequently in a group of 37 Greek patients with clinical suspicion of NPC disease and in a group of 90 healthy Greek individuals, by the use of Haplore software. RESULTS: Two novel NPC1 mutations, [IVS23 + 3insT (c.3591 + 3insT) and p. K1057R (c.3170A > C)] were identified and each mutation was associated with a specific haplotype. One of the patients was entered to early treatment with miglustat and has presented no overt neurological impairment after 11.5 years. CONCLUSIONS: The splicing mutation IVS23 + 3insT was associated in homozygocity with a severe biochemical and clinical phenotype. A possible founder effect for this mutation was demonstrated in the Greek Island, as well as a different origin for each novel mutation. Longitudinal follow-up may contribute to clarify the possible effect of early miglustat therapy on the patient compound heterozygous for the two novel mutations.
Subject(s)
Carrier Proteins/genetics , Membrane Glycoproteins/genetics , Mutation , Niemann-Pick Disease, Type C/genetics , Child , Child, Preschool , Female , Founder Effect , Greece , Humans , Intracellular Signaling Peptides and Proteins , Male , Niemann-Pick C1 Protein , PedigreeABSTRACT
A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on ß-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.
Subject(s)
Dimerization , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosylceramidase/antagonists & inhibitors , Xylitol/chemical synthesis , Xylitol/pharmacology , Catalytic Domain , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemistry , Fibroblasts/drug effects , Fibroblasts/enzymology , Gaucher Disease/enzymology , Glucosylceramidase/chemistry , Glucosylceramidase/metabolism , Humans , Protein Transport , Stereoisomerism , Xylitol/chemistryABSTRACT
Correction for 'Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity' by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681-3705.
ABSTRACT
BACKGROUND: Maple syrup urine disease (MSUD) is a rare metabolic disorder, affecting the metabolism of branched chain amino-acids (Valine, Leukine, Isoleukine). We present a rare case of rhegmatogenous retinal detachment (RRD) in a MSUD patient. CASE PRESENTATION: We performed amino acid analysis of aqueous humour, vitreous and serum samples obtained during surgery from a 24 year old female MSUD patient successfully operated on RRD. Serum values for a-amino-butyric acid, valine, isoleucine, leucine, tyrosine, phenylalanine, ornithine and histidine were low, while values for citrulline, methionine and lysine were borderline low, all attributed to the patient's special diet. Serum glutamate was above normal, probably due to the breakdown of glutamine to glutamate. In the aqueous and vitreous the amino acids implicated in MSUD (Valine, Leukine Isoleukine), were within normal range. Glutamate was absent in the vitreous and presented low levels in the aqueous. Glutamate has been reported to play an important role in retinal damage. Elevated glutamate levels have been reported in vitreous specimens from patients subjected to vitrectomy or buckling surgery for RRD. In MSUD, glutamate has been implicated in the pathogenesis of brain damage. Low levels of glutamate have been observed in the cerebellum of experimental MSUD animals, as well as postmortem brain tissue from a child that died of leucine intoxication. The reduction was attributed to the elevation of a-ketoisocaproic which reverses the net direction of nitrogen flow. It could be argued that this could impact on amino acid concentration in aqueous and vitreous fluids. CONCLUSIONS: Although no definite conclusions can be drawn by this extremely rare case, the low vitreous and aqueous levels of Glutamate is an interesting finding. Further studies are needed to provide a better insight in the role of amino acids as neurotransmitters in the human eye in health and disease.
Subject(s)
Amino Acids/analysis , Aqueous Humor/chemistry , Maple Syrup Urine Disease/metabolism , Retinal Detachment/metabolism , Vitreous Body/chemistry , Female , Humans , Retinal Detachment/surgery , Young AdultABSTRACT
BACKGROUND: Reduced expression of lysosomal-associated membrane protein 2a and heatshock-cognate 70 proteins, involved in chaperone-mediated autophagy and of glucocerebrosidase, is reported in PD brains. The aim of this study was to identify systemic alterations in lysosomal-associated membrane protein 2a, heatshock cognate-70, and glucocerebrosidase levels/activity in peripheral blood mononuclear cells from PD patients. METHODS: Protein/mRNA levels were assessed in PD patients from genetically undetermined background, alpha-synuclein (G209A/A53T), or glucocerebrosidase mutation carriers and age-/sex-matched controls. RESULTS: Heatshock cognate 70 protein levels were reduced in all PD groups, whereas its mRNA levels were decreased only in the genetically undetermined group. Glucocerebrosidase protein levels were decreased only in the genetic PD groups, whereas increased mRNA levels and decreased activity were detected only in the glucocerebrosidase mutation group. CONCLUSIONS: Reduced heatshock cognate-70 levels are suggestive of an apparent systemic chaperone-mediated autophagy dysfunction irrespective of genetic background. Glucocerebrosidase activity may serve as a screening tool to identify glucocerebrosidase mutation carriers with PD.
Subject(s)
Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Parkinson Disease/pathology , Case-Control Studies , Female , Gene Expression Regulation/genetics , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , HSC70 Heat-Shock Proteins/metabolism , Humans , Lysosomal Membrane Proteins/genetics , Lysosomal Membrane Proteins/metabolism , Lysosomes/genetics , Male , Mutation/genetics , Parkinson Disease/genetics , RNA, Messenger/metabolism , alpha-Synuclein/genetics , alpha-Synuclein/metabolismABSTRACT
Plasmalogens represent a unique class of phospholipids. Reduced red blood cell plasmalogen levels in Gaucher disease patients were reported, correlating to total disease burden. The relation between plasmalogen abnormalities in Gaucher disease patients and primary glycosphingolipid abnormalities, malonyldialdehyde levels, an indicator of lipid peroxidation, and the total antioxidant status was further investigated. Significant reduction of C16:0 and C18:0 plasmalogens in red blood cells of Gaucher disease patients was confirmed. In parallel, a significant increase in the glucosylceramide/ceramide ratio in red blood cell membranes, as well as an average 200-fold increase in plasma glucosylsphingosine levels was observed. Red blood cell malonyldialdehyde levels were significantly increased in patients, whereas their total antioxidant status was significantly reduced. A negative correlation between plasmalogen species and glucosylceramide, ceramide, glucosylceramide/ceramide ratio, glucosylsphingosine and malonyldialdehyde, significant for the C16:0 species and all the above parameters with the exception of malonyldialdehyde levels, was found along with a positive non-significant correlation with the total antioxidant status. Our results indicate that increased lipid peroxidation and reduced total antioxidant status exist in Gaucher disease patients. They demonstrate a clear link between plasmalogen levels and the primary glycolipid abnormalities characterizing the disorder and an association with the increased oxidative stress observed in Gaucher disease patients.
Subject(s)
Gaucher Disease/metabolism , Lipid Metabolism , Oxidative Stress , Plasmalogens/metabolism , Adolescent , Adult , Aged , Case-Control Studies , Ceramides/metabolism , Child , Child, Preschool , Erythrocytes/metabolism , Gaucher Disease/blood , Glucosylceramides/metabolism , Humans , Lipid Peroxidation , Middle Aged , Young AdultABSTRACT
It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson's disease. A plethora of evidence suggests that disturbed α-Synuclein homeostasis is the link between Gaucher disease and Parkinson's disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated α-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of α-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized α-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating α-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of α-Synuclein oligomerization in this system.
Subject(s)
Gaucher Disease , Parkinson Disease , Humans , Gaucher Disease/drug therapy , Gaucher Disease/metabolism , alpha-Synuclein/metabolism , Parkinson Disease/complications , Enzyme Replacement Therapy , Erythrocytes/metabolism , Glucosylceramidase/therapeutic use , Glucosylceramidase/metabolismABSTRACT
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α-glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at http://www.pompecenter.nl aims to list all variants and their effect. This update reports on 94 variants. We examined 35 novel and 34 known mutations by site-directed mutagenesis and transient expression in COS-7 cells or HEK293T cells. Each of these mutations was given a severity rating using a previously published system, based on the level of acid α-glucosidase activity in medium and transfected cells and on the quantity and quality of the different molecular mass species in the posttranslational modification and transport of acid α-glucosidase. This approach enabled to classify 55 missense mutations as pathogenic and 13 as likely nonpathogenic. Based on their nature and the use of in silico analysis (Alamut® software), 12 of the additional 25 novel mutations were predicted to be pathogenic including 4 splicing mutations, 6 mutations leading to frameshift, and 2 point mutations causing stop codons. Seven of the additional mutations were considered nonpathogenic (4 silent and 3 occurring in intron regions), and 6 are still under investigation.
Subject(s)
Databases, Genetic , Glycogen Storage Disease Type II/genetics , alpha-Glucosidases/genetics , Genetic Predisposition to Disease , Humans , MutationABSTRACT
Lysosomal protein 2 (LIMP2), the product of the scavenger receptor class B member 2 (SCARB2) gene, is a ubiquitously expressed transmembrane protein that is the mannose-6-phosphate-independent receptor for glucocerebrosidase (ß-GCase); a deficiency in this protein causes Gaucher disease. Several studies have shown a link between mutations in the ß-GCase gene and diseases characterized clinically by Parkinsonism and by the presence of Lewy body-related pathology. We hypothesized that genetic variants in the SCARB2 gene could be risk factors for Parkinson's disease (PD). A candidate-gene study of 347 Greek patients with sporadic PD and 329 healthy controls was conducted to investigate the association between 5 polymorphisms in the SCARB2 gene (rs6824953, rs6825004, rs4241591, rs9991821, and rs17234715) and the development of PD. The single-locus analysis for the 5 polymorphisms revealed an association only for the rs6825004 polymorphism: the generalized odds ratio (OR(G) ) was 0.68 (95% confidence interval [CI], 0.51-0.90), and the OR for the allelic test was OR = 0.71 (95% CI, 0.56-0.90). Haplotype analysis showed an association for the GCGGT haplotype (P < .01). Our study supports a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding.
Subject(s)
Genetic Predisposition to Disease/genetics , Lysosomal Membrane Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Scavenger/genetics , Case-Control Studies , Chi-Square Distribution , Female , Gene Frequency , Genetic Association Studies , Genotype , Greece , Humans , Male , Odds Ratio , Retrospective StudiesABSTRACT
An increasing number of clinical, neuropathological and experimental evidence linking Gaucher disease and a spectrum of synucleinopathies, including Parkinson's disease (PD) has emerged over the last decade. In particular, several studies, despite individual differences, have shown that mutations in the ß-glucocerebrosidase gene (GBA) are a risk factor for PD. Recently a study from Northern Greece has shown a significant overrepresentation of such mutations only in patients with early onset PD. In the present study 8 different GBA mutations covering 87% of the mutations identified in Gaucher disease patients diagnosed in Greece were investigated in two ethnic Greek cohorts of patients with sporadic Parkinson's disease. Cohort A included patients residing and originating from Thessaly, Central Greece (n=100) and cohort B included patients residing and/or originating from the greater area of Athens (n=105). Age-gender-ethnicity matched healthy individuals from the same areas were included as controls (n=206). In patients of cohort A 11 carriers of GBA mutations were identified (5/11:N370S, 2/11:L444P, 2/11: D409H;H255Q, 1/11:H255Q, 1/11D409H) as opposed to 3 in the controls (n=105) (1/3:N370S, 1/3:H255Q, 1/3:Y108C) (p=0.021, OR 4.2, 95% CI=1.14-15.54). In patients of cohort B 10 carriers of GBA mutations were identified (4/10:L444P, 4/10:D409H;H255Q, 1/10:N370S, 1/10:IVS10-1GâA) as opposed to 4 in controls (n=101) (3/4:N370S, 1/4:L444P). However the difference was not statistically significant (p=0.113, OR 2.5, 95% CI=0.77-8.42). In both cohorts, patients with PD harboring a GBA mutation had an earlier onset of symptoms than non-carriers (p=0.034, p=0.004). The overall difference in the number of carriers identified in PD patients and controls was statistically significant (p=0.006; OR 3.24; 95% CI=1.35-7.81). The association was reinforced in the early onset PD patients (EOPD; n=28, p=0.000, OR 11.37; 95% CI=3.73-34.6). In conclusion GBA mutations were identified with increased frequency in both geographical cohorts of patients with sporadic PD studied compared to control individuals, with the difference being statistically significant only in cohort A. An impressive association with EOPD was found and one third of the EOPD patients examined harbored a GBA mutation. Qualitative differences regarding the type of mutations and/or their relative frequencies were observed between cohorts A and B of PD patients. Genetic and/or environmental factors may account for the observed differences.
Subject(s)
Glucosylceramidase/genetics , Mutation/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Greece , Heterozygote , Humans , Male , Middle Aged , Restriction MappingABSTRACT
Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live-births in France to 1.21 per 100,000 live-births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6-7 years follow-up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype-phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available.
Subject(s)
Hydrolases/genetics , Mucopolysaccharidosis III/epidemiology , Mucopolysaccharidosis III/genetics , Adolescent , Age Factors , Child , Child, Preschool , Disease Progression , France/epidemiology , Greece/epidemiology , Humans , Hydrolases/metabolism , Incidence , Infant , Liver/metabolism , Mucopolysaccharidosis III/pathology , Mutation/genetics , Retrospective Studies , United Kingdom/epidemiologyABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0060674.].