15 research outputs found
Exon dosage variations in Brazilian patients with Parkinson's disease: Analysis of SNCA, PARKIN, PINK1 and DJ-1 genes
Abstract. Parkinson's disease is one of the most common neurodegenerative disorders associated with aging, reaching ⌠2% of individuals over 65 years. Knowledge achieved in the last decade about the genetic basis of Parkinson's disease clearly shows that genetic factors play an important role in the etiology of this disorder. Exon dosage variations account for a high proportion of Parkinson's disease mutations, mainly for PARKIN gene. In the present study, we screened genomic rearrangements in SNCA, PARKIN, PINK1 and DJ-1 genes in 102 Brazilian Parkinson's disease patients with early onset (age of onset 50 years), using the multiplex ligation-dependent probe amplification method. Family history was reported by 24 patients, while 78 were sporadic cases. Screening of exon dosage revealed PARKIN and PINK1 copy number variations, but no dosage alteration was found in SNCA and DJ-1 genes. Most of the carriers harbor heterozygous deletions or duplications in the PARKIN gene and only one patient was found to have a deletion in PINK1 exon 1. Data about dosage changes are scarce in the Brazilian population, which stresses the importance of including exon dosage analysis in Parkinson's disease genetic studies
Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations:Experience from the MJFF Global Genetic Parkinson's Disease Project
Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.</p
Finding FMR1 mosaicism in Fragile X syndrome
ObjectiveAlmost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism.MethodsMutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR).ResultsFour patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions.ConclusionThe authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated
Chromosome 6q deletion: Report of a new case and review of the literature
The authors report an additional case of partial monosomy of the long arm of chromosome 6 [46,XY,del (6)(q22 <font SIZE="3" face="Symbol">Âź</font> qter)]. Our patient has a large segment beyond 6q25 deleted, then severe psychomotor retardation is expected to occur
Finding <i>FMR1</i> mosaicism in Fragile X syndrome
<p><b>OBJECTIVE</b>: Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (<i>FMR1</i>). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism.</p> <p><b>METHODS</b>: Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR).</p> <p><b>RESULTS</b>: Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of <i>FMR1</i> gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions.</p> <p><b>CONCLUSION</b>: The authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated.</p
Geleophysic dysplasia: Report on two sibs
The authors describe two additional cases of Geleophysic dysplasia in siblings, which is a rare autosomal recessive disorder of glycoprotein metabolism whose basic defects remain to be determined.<br>Os autores descrevem dois novos casos de displasia GeleofĂsica em irmĂŁos, uma doença autossĂŽmica recessiva rara do metabolismo de glicoproteĂnas cujo defeito bĂĄsico ainda nĂŁo foi determinado
Genetic Analysis of PARK2 and PINK1 Genes in Brazilian Patients with Early-Onset Parkinsonâs Disease
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Previous issue date: 2013Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de GenĂ©tica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. LaboratĂłrio de GenĂ©tica Humana. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Hospital UniversitÂŽario Clementino Fraga Filho. Rio de Janeiro, RJ, Brasil.Santa Casa da MisericĂłrdia do Rio de Janeiro. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Centro BiomĂ©dico. Faculdade de CiĂȘncias MĂ©dicas. Rio de Janeiro, RJ, Brasil.Universidade Federal de GoiĂĄs. Hospital das ClĂnicas. NĂșcleo de NeurociĂȘncias. GoiĂąnia, GO, Brasil / Instituto Integrado de NeurociĂȘncias. GoiĂąnia, GO, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de GenĂ©tica. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de GenĂ©tica. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de GenĂ©tica. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de GenĂ©tica. Rio de Janeiro, RJ, Brasil.Parkinsonâs disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the
age of 65. The etiology of Parkinsonâs disease is complex, with the involvement of gene-environment interactions. Although it
is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5â10% of all cases. In the present
study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset
Parkinsonâs disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic
mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene,
only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that
PARK2 pointmutations aremore common in Brazilian early-onset Parkinsonâs disease patients (2.9%) than PINK1 missense variants
(0%), corroborating other studies worldwide
Copy-number gains of HUWE1 due to replication-and recombination-based rearrangements
We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3âČ untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.Guy Froyen ... Tulika Bose, Mark A. Corbett ... et al