ABSTRACT
An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.
Subject(s)
Autistic Disorder , Intellectual Disability , Female , Humans , Male , Autistic Disorder/genetics , Intellectual Disability/genetics , Intellectual Disability/complications , Muscle Hypotonia/genetics , Muscle Hypotonia/complications , Phenotype , Syndrome , Transcription Factors/geneticsABSTRACT
Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.
Subject(s)
Endosomes , Intellectual Disability , Vesicular Transport Proteins , Humans , Alleles , Endosomes/genetics , Endosomes/metabolism , Intellectual Disability/genetics , Lysosomes/genetics , Lysosomes/metabolism , Mutation , Protein Transport/genetics , Vesicular Transport Proteins/geneticsABSTRACT
PURPOSE: The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation. METHODS: Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease. RESULTS: We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. CONCLUSION: Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.
Subject(s)
Motor Neuron Disease , Neurodegenerative Diseases , Humans , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/metabolism , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/metabolism , Motor Neuron Disease/genetics , Motor Neuron Disease/metabolismABSTRACT
GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson's disease (PD) and tetrahydrobiopterin (BH4 )-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood-onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP-associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.
Subject(s)
GTP Cyclohydrolase/genetics , Mutation/genetics , Spastic Paraplegia, Hereditary/genetics , Adult , Canada , Child , Female , Humans , Levodopa/therapeutic use , Male , Middle Aged , Parkinsonian Disorders/genetics , Pedigree , Phenotype , Spastic Paraplegia, Hereditary/drug therapy , Twins, Monozygotic/geneticsABSTRACT
BACKGROUND: Epidemiological studies have reported an association between Parkinson's disease (PD) and restless legs syndrome. OBJECTIVES: We aimed to use genetic data to study whether these 2 disorders are causally linked or share genetic architecture. METHODS: We performed two-sample Mendelian randomization and linkage disequilibrium score regression using summary statistics from recent genome-wide meta-analyses of PD and restless legs syndrome. RESULTS: We found no evidence for a causal relationship between restless legs syndrome (as the exposure) and PD (as the outcome, inverse variance-weighted; b = -0.003, SE = 0.031, P = 0.916; F statistic = 217.5). Reverse Mendelian randomization also did not demonstrate any causal effect of PD on restless legs syndrome (inverse variance-weighted; b = -0.012, SE = 0.023, P = 0.592; F statistic = 191.7). Linkage disequilibrium score regression analysis demonstrated lack of genetic correlation between restless legs syndrome and PD (rg = -0.028, SE = 0.042, P = 0.507). CONCLUSIONS: There was no evidence for a causal relationship or genetic correlation between restless legs syndrome and PD. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants. © 2021 International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease , Restless Legs Syndrome , Causality , Humans , Parkinson Disease/complications , Parkinson Disease/epidemiology , Parkinson Disease/genetics , Restless Legs Syndrome/epidemiology , Restless Legs Syndrome/geneticsABSTRACT
BACKGROUND: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. OBJECTIVES: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD. METHODS: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. RESULTS: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found. CONCLUSIONS: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease , Age of Onset , DNA Copy Number Variations/genetics , Female , Heterozygote , Humans , Male , Mutation , Parkinson Disease/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
BACKGROUND: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). OBJECTIVES: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. METHODS: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. RESULTS: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. CONCLUSIONS: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.
Subject(s)
Spastic Paraplegia, Hereditary , ATP-Dependent Proteases , ATPases Associated with Diverse Cellular Activities/genetics , Canada , Humans , Metalloendopeptidases/genetics , Mutation/genetics , Paraplegia , Spastic Paraplegia, Hereditary/genetics , Transcription FactorsABSTRACT
OBJECTIVE: To estimate the minimum prevalence of adult hereditary ataxias (HA) and spastic paraplegias (HSP) in Eastern Quebec and to evaluate the proportion of associated mutations in identified genes. METHODS: We conducted a descriptive cross-sectional study of patients who met clinical criteria for the diagnosis of HA (n = 241) and HSP (n = 115) in the East of the Quebec province between January 2007 and July 2019. The primary outcome was the prevalence per 100,000 persons with a 95% confidence interval (CI). The secondary outcome was the frequency of mutations identified by targeted next-generation sequencing (NGS) approach. Minimum carrier frequency for identified variants was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. RESULTS: The minimum prevalence of HA in Eastern Quebec was estimated at 6.47/100 000 [95% CI; 6.44-6.51]; divided into 3.73/100 000 for autosomal recessive (AR) ataxias and 2.67/100 000 for autosomal dominant (AD) ataxias. The minimum prevalence of HSP was 4.17/100 000 [95% CI; 4.14-4.2]; with 2.05/100 000 for AD-HSP and 2.12/100 000 for AR-HSP. In total, 52.4% of patients had a confirmed genetic diagnosis. AR cerebellar ataxia type 1 (2.67/100 000) and AD spastic paraplegia SPG4 (1.18/100 000) were the most prevalent disorders identified. Mutations were identified in 23 genes and molecular alterations in 7 trinucleotides repeats expansion; the most common mutations were c.15705-12 A > G in SYNE1 and c.1529C > T (p.A510V) in SPG7. CONCLUSIONS: We described the minimum prevalence of genetically defined adult HA and HSP in Eastern Quebec. This study provides a framework for international comparisons and service planning.
Subject(s)
Cerebellar Ataxia , Spastic Paraplegia, Hereditary , Adult , Cross-Sectional Studies , Humans , Mutation , Paraplegia , Quebec/epidemiology , Spastic Paraplegia, Hereditary/epidemiology , Spastic Paraplegia, Hereditary/geneticsABSTRACT
BACKGROUND: Altered innate immune function plays an important role in the initiation of inflammatory response in Behcet's disease (BD). Toll-like receptors (TLRs) are the master regulators of the innate immune system. Because the role of TLRs remains unknown in the pathogenesis of BD, the present study aimed to evaluate the expression levels and methylation status of the TLR2 and TLR4 promoters in patients with BD. METHODS: In the present study, Iranian Azeri BD patients (n = 47) with an active (n = 22) and inactive (n = 25) period, and healthy controls (n = 61), were matched according to age, sex and ethnicity. TLR2 and TLR4 genes promoter CpG islands were predicted with the Eukaryotic Promoter Database (https://epd.vital-it.ch). Methylated DNA immunoprecipitation (MeDIP) was conducted. RESULTS: The results showed that mRNA of TLR4 was significantly increased in the peripheral blood mononuclear cells (PBMCs) of BD patients with an active phase compared to the control group. Differences in mRNA of TLR4 between the inactive BD and control groups were not significant. Differences in TLR2 mRNA levels in the PBMCs of the active and inactive phase BD and control groups were not significant. The methylation rate of TLR4 gene promoter was significantly lower in the active and inactive BD groups compared to the control group. The difference between the active and inactive BD groups was not significant. There was no significant difference in the methylation rates of the TLR2 gene between studied groups. CONCLUSIONS: Our preliminary findings suggest that the hypomethylation of TLR4 gene may be involved in the pathogenesis of BD via increasing TLR4 expression.
Subject(s)
Behcet Syndrome/genetics , DNA Methylation/genetics , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/genetics , Adult , Behcet Syndrome/epidemiology , Behcet Syndrome/pathology , CpG Islands/genetics , Female , Humans , Immunity, Innate/genetics , Iran/epidemiology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Male , Promoter Regions, Genetic/geneticsABSTRACT
PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.
Subject(s)
Charcot-Marie-Tooth Disease , Spastic Paraplegia, Hereditary , Alleles , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/genetics , Humans , Mutation , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/genetics , Exome SequencingABSTRACT
More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.
Subject(s)
Carrier Proteins/genetics , Microfilament Proteins/genetics , Nerve Degeneration/genetics , Spastic Paraplegia, Hereditary/genetics , Animals , Axons/pathology , Carrier Proteins/chemistry , Computer Simulation , Female , Heterozygote , Humans , Male , Mice , Microfilament Proteins/chemistry , Models, Animal , Mutation/genetics , Nerve Degeneration/physiopathology , Phenotype , Protein Conformation , Spastic Paraplegia, Hereditary/epidemiology , Zebrafish/geneticsABSTRACT
BACKGROUND: miR-221 and miR-222 are homologous miRNAs located in tandem, within 1 kb from each other, on human x chromosome. Recent studies declared that microRNA-222 is aberrantly expressed in various malignancies. The goal of this research was to measure the expression level of has-miR-222-3P and reveal its diagnostic and prognostic importance in breast malignancy. METHODS: In this study, 40 pairs of cancerous and matched adjacent non-cancerous breast tissue were collected from patients, and real-time PCR was used to measure the relative expression of miR-222. RESULTS: Our study clarified that microRNA-222 is enhanced in tumor tissues in comparison with normal tissue margins (p ≤ 0.05) and overexpression of miR-222 was not associated with clinicopathological factors such as age, BMI, menopausal status, histological type, grade, stage, tumor size, lymph node metastasis (p > 0.05). The receiver operating characteristic (ROC) curve analysis displayed an optimum cutoff point of < 4.17 to prove that miR-222 is a useful biomarker in breast cancer diagnosis. CONCLUSIONS: Our findings on miR-222 suggest that it could be a potentially useful target for control and management of breast malignancy.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Adult , Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Female , Humans , Middle Aged , Prognosis , ROC CurveABSTRACT
BACKGROUND: miRNA-221 and miRNA-222 are two homologous microRNAs, the high-expression levels of which have been commonly demonstrated in the most current human cancer types as well as breast cancer. The purpose of this research was to determine the clinical value of measuring the expression level of hsa-miR-221-3p in breast cancer tissues and evaluate its biological and prognostic importance in breast cancer (BC). METHODS: A total of 40 tumor samples and matched tumor-free margin specimens were obtained during surgery from patients with BC. After total RNA extraction and cDNA synthesis, the relative expression level of hsa-miR221-3p in tumor and marginal tissues was examined by quantitative real-time PCR. Moreover, the association between hsa-miR-221-3p expression and clinicopathological features of patients was detected. RESULTS: The relative expression level of hsa-miR-221-3p in BC tissues was significantly higher than that in adjacent noncancerous breast biopsies (p ≤ 0.0001). Also, there was no significant association between hsa-miR-221-3p expression with clinicopathological characteristics (p > 0.05). The receiver operating characteristic (ROC) curve analyses also represented an optimum cutoff point of < 4.34 to show that hsa-miR-221-3p is an effective molecular biomarker for BC diagnosis. CONCLUSIONS: This study illustrated that analysis of hsa-miR-221-3p relative gene expression may be applied as a biomarker for screening BC patients and could be a substantial tool in diagnosis and prognosis. Also, that could be advantageous in decreasing surgical mistakes in tumor elimination through the surgery and enhancing all over the progression of surgery with reformed tumor clearance.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Margins of Excision , MicroRNAs/genetics , Adult , Aged , Breast Neoplasms/diagnosis , Breast Neoplasms/surgery , Cross-Sectional Studies , Humans , Middle Aged , Prognosis , Sensitivity and SpecificityABSTRACT
Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone.
Subject(s)
Bone Neoplasms/genetics , Bone Neoplasms/secondary , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Animals , Bone Neoplasms/metabolism , Breast Neoplasms/metabolism , Female , HumansABSTRACT
BACKGROUND: MDM4 is a negative regulator of the p53 tumor suppression pathway. Recent studies have revealed that the rs4245739 A>C polymorphism of MDM4 in the 3ï¢-untranslated region makes it a miR-191 target site which leads to lower MDM4 expression. This study is aimed to detect if rs4245739 single nucleotide polymorphism (SNP) of the MDM4 gene influences the breast cancer development in Iranian-Azeri women. METHODS: Blood samples were taken from 260 healthy controls and 220 breast cancer women with ethnicity of Iranian-Azeri. Genotyping was done using Tetra-ARMS PCR. RESULTS: Alleles of MDM4 rs4245739 SNP had no significant different frequency between patients and controls (p > 0.05). Additionally, genotypes of MDM4 rs4245739 SNP did not increase or decrease breast cancer risk in patients when compared to healthy women. Also, there was no significant association between the alleles of MDM4 rs4245739 SNP and clinicopathological factors (p > 0.05). CONCLUSIONS: Considering the lack of association between MDM4 rs4245739 polymorphism and breast cancer, rs4245739 polymorphism of this gene seems to have no significant role in the pathophysiology of the disease.
Subject(s)
3' Untranslated Regions/genetics , Breast Neoplasms/genetics , Genetic Predisposition to Disease , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins/genetics , Adult , Age of Onset , Breast Neoplasms/pathology , Case-Control Studies , Cell Cycle Proteins , Female , Genotype , Humans , Iran , Middle Aged , Proto-Oncogene Proteins c-mdm2/geneticsABSTRACT
INTRODUCTION: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). We aimed to study genetic and clinical characteristics of SPG4 across Canada. METHODS: The SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations. RESULTS: We identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and clinically isolated syndrome, and novel or rarely reported signs and symptoms seen in SPG4 patients. CONCLUSION: Our study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.
Subject(s)
Spastic Paraplegia, Hereditary , Spastin , Adenosine Triphosphatases/genetics , DNA Copy Number Variations , Humans , Mutation , Paraplegia/genetics , Phenotype , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/genetics , Spastin/geneticsABSTRACT
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.
Subject(s)
Parkinson Disease , REM Sleep Behavior Disorder , Synucleinopathies , Humans , REM Sleep Behavior Disorder/genetics , Genome-Wide Association Study , Parkinson Disease/genetics , BrainABSTRACT
BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected pâ=â0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
Subject(s)
Parkinson Disease , REM Sleep Behavior Disorder , Saposins/genetics , Synucleinopathies , Glucosylceramidase/genetics , Humans , Parkinson Disease/complications , REM Sleep Behavior Disorder/diagnosisABSTRACT
Parkinson's disease (PD) is the second main neurodegenerative disease causing motor abnormalities in the middle-aged and old individuals. In some cases, cognitive dysfunction also occurs. The clinical signs of PD are bradykinesia, rigidity and resting tremor. As these signs might be detected in other neurological conditions such as multiple systems atrophy and corticobasal degeneration, it is necessary to find specific and sensitive markers for this disorder. Non-coding RNAs are implicated in the different PD-associated features such as α-synuclein expression and Lewy body construction, mitochondrial dysfunction, apoptosis, neuroinflammation and defects in glial cell-derived neurotrophic factor. Several researches have confirmed dysregulation of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in brain tissues, plasma exosomes and leukocytes of affected individuals or animal models of PD. A number of these transcripts directly regulate the neurodegenerative process in PD. In the current study, we review the current data about dysregulation of ncRNAs and the role of their genomic variants in the pathogenesis of PD.