Percorrer por autor "Oliveira, Jorge"
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- Anoctamin 5: A New Candidate Gene For Portuguese Patients With Adult Onset Limb-Girdle Muscular DystrophyPublication . Santos, Rosário; Vieira, Emília; Moutinho, Ariana; Oliveira, Jorge; Negrão, Luís; Bronze-da-Rocha, ElsaIntroduction: The limb-girdle muscular dystrophies (LGMDs) show wide genetic and clinical heterogeneity. Recessive mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel of the anoctamin family, have been recently identified in families with LGMD type 2L and non-dysferlin distal muscular dystrophy (MMD3). The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy, whereas MMD3 is associated with distal weakness, particularly of calf muscles. Methods: In a group of 125 patients with clinical LGMD, but no mutations in other candidate genes involved in LGMD, we screened the “common” mutation c.191dupA. Subsequently, in 10 selected patients the entire coding region of ANO5 was fully sequenced. Results: Mutations were identified in 4 patients (3 families), all presenting hyperCKemia and adult onset proximal lower limb weakness. The common mutation c.191dupA was found in one family (2 patients), in a homozygous state. This mutation results in a frameshift with a consequent premature stop codon (p.Asn64LysfsX15), triggering nonsense-mediated mRNA decay. A novel substitution identified in exon 18 (c.2012A>G), predictably a missense mutation, was shown to in fact create a new donor splice site. mRNA studies confirmed aberrant splicing in exon 18, promoting an in-frame deletion of 18 nucleotides (r.2012_2029del) that results in a truncated protein (p.Tyr671_Val677delinsPhe). The third patient had a heterozygous nucleotide substitution in exon 8, c.692G>T, predicted to result in a missense mutation (p.Gly231Val). The Gly231 residue, localized in the N-terminal domain, is evolutionarily conserved. In this patient the second mutation has not yet been identified. Conclusion: Although c.191dupA was detected in only 1/125 patients, systematic sequencing of ANO5 in 10 patients revealed a further two positive cases, indicating that the anoctaminopathies may account for a reasonable number of our LGMD patients.
- Atrofias Musculares Espinhais: do estudo genético ao registo de doentesPublication . Oliveira, Jorge; Rodrigues, Luisa; Maia, Nuno; Oliveira, Marcia E.; Santos, RosárioA Atrofia Muscular Espinhal (AME) caracteriza-se pela degeneração das células do corno anterior da medula espinhal, resultando em fraqueza e atrofia muscular progressiva. O espectro clínico da doença é variável, desde formas graves de inicio neonatal (tipo I/Werdnig-Hoffman, MIM#253400) a fenótipos mais ligeiros com apresentação na idade adulta (tipo IV, MIM#271150). Considerando a frequência de portadores de AME na nossa população (1/52)1, estima-se que a incidência da doença em Portugal seja ~1/10800. A AME resulta de mutações no gene SMN1, no entanto foram já descritos outros genes (nomeadamente IGHMBP2, ATP7A, GARS, TRPV4 e PLEKHG5) associados a atrofias musculares espinhais mais raras. Desde 1994 foram estudados, na unidade de Genética Molecular, 549 doentes com suspeita clínica de AME. Foi confirmado o envolvimento do gene SMN1 em 223 doentes (40,6%) pertencentes a 219 famílias. Nestes doentes, o defeito genético mais frequente consiste na delecção em homozigotia do gene SMN1 (91,9%). Em 18 doentes (8,1%) foram identificadas mutações pontuais: c.346A>T (n=1), c.524delC (n=1) c.734dupC (n=1) e c.770_780dup (n=15). De forma a possibilitar o acesso de destes doentes a futuros ensaios clínicos, encontra-se em implementação o registo nacional de doentes com AME como previamente acordado com a SPEDNM e a rede internacional TREAT-NMD. Considerando o número de doentes com suspeita de AME sem confirmação molecular e a possível sobreposição fenotípica com outras patologias (distrofias, CMT e ALS), torna-se pertinente a re-avaliação clínica destes doentes. Esta permitirá o alargamento do estudo molecular a outros genes candidatos e eventualmente a identificação de novas causas genéticas para a AME recorrendo à análise genómica em larga escala.
- Base de dados internacional de variantes genéticas do gene MTM1: contributos para o perfil epidemiológico da miopatia miotubularPublication . Oliveira, Jorge; Oliveira, Rosário; Santos, Márcia
- Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange SyndromePublication . Oliveira, Jorge; Dias, Cristina; Redeker, Egbert; Costa, Eurico; Silva, João; Lima, Margarida Reis; Den Dunnen, Johan T.; Santos, RosárioThe establishment of Locus Specific Databases (LSDB) is a crucial aspect for the Human Genetics field and one of the aims of the Human Variation Project. We report the development of a publicly accessible LSDB for the NIPBL gene (http://www.lovd.nl/NIPBL) implicated in Cornelia de Lange Syndrome (CdLS). This rare disorder is characterized by developmental and growth retardation, typical facial features, limb anomalies, and multiple organ involvement. Mutations in the NIPBL gene, the product of which is involved in control of the cohesion complex, account for over half of the patients currently characterized. The NIPBL LSDB adopted the Leiden Open Variation database (LOVD) software platform, which enables the comprehensive Web-based listing and curation of sequence variations and associated phenotypical information. The NIPBL-LOVD database contains 199 unique mutations reported in 246 patients (last accessed April 2010). Information on phenotypic characteristics included in the database enabled further genotype–phenotype correlations, the most evident being the severe form of CdLS associated with premature termination codons in the NIPBL gene. In addition to the NIPBL LSDB, 50 novel mutations are described in detail, resulting from a collaborative multicenter study. Hum Mutat 31:1216–1222, 2010. © 2010 Wiley-Liss, Inc.
- Doenças musculares metabólicas e do neurónio motorPublication . Oliveira, Jorge
- Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptomsPublication . Duarte, Sofia; Oliveira, Jorge; Santos, Rosário; Pereira, Pedro; Barroso, Cândida; Conceição, Isabel; Evangelista, TeresinhaINTRODUCTION: Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH). METHODS: Patients with muscle symptoms in adulthood, who had features compatible with CCD/MmD, underwent clinical, histological, and genetic (RYR1 and SEPN1 genes) evaluations. Published cases of CCD and MmD with adult onset were also reviewed. RESULTS: Eight patients fulfilled the criteria for further analysis. Five RYR1 mutations, 4 of them unreported, were detected in 3 patients. Compound heterozygosity was proven in 1 case. CONCLUSIONS: To our knowledge, this is the only report of adult onset associated with recessive RYR1 mutations and central core/multiminicores on muscle biopsy. Although adult patients with CCD, MmD, and minimally symptomatic MH with abnormal muscle biopsy findings usually have a mild clinical course, differential diagnosis and carrier screening is crucial for prevention of potentially life-threatening reactions to general anesthesia.
- Dystrophie musculaire congénitale de type 1A – une série pédiatriquePublication . Cancelinha, Candida; Cost, Carmen; Oliveira, Jorge; Fineza, IsabelLa dystrophie musculaire congénitale de type 1A (MCD1A) représente 30-50% des dystrophies musculaires congénitales (MCD) dans la population européenne. Méthodes: Étude rétrospective descriptive d'une consultation neuromusculaire dans un hôpital pédiatrique. Analyse des dossiers des patients ayant un diagnostic de MCD1A, pour la caractérisation clinique, démarche diagnostique et évolution. Résultats: Sur un total de 25 cas de MCD ont été inclus 14 (57%) patients (11 familles) avec MCD1A, quatre familles consanguines. Hypotonie néonatale et faiblesse musculaire ont été la principale forme de présentation, tous les cas ont développé des contractures articulaires dans la première année de vie. Le diagnostic a été fait par biopsie musculaire, le étude immunohistochimique a révélé un déficit en mérosine et/ ou l'imagerie suggérant la leucodystrophie, avec confirmation génétique dans tous les cas. La moitié des patients ont acquis une position assise sans appui, la totalité se déplace en fauteuil roulant; seulement deux cas ont montré une légère déficit cognitive. L’insuffisance respiratoire chronique a été le principal comorbidité, 10 (71%) patients nécessitant d’une ventilation non invasive. Trois patients (21%) ont requis la gastrostomie, douze (86%) développé scoliose, quatre (29%) ont été opérés. Quatre patients (29%) avaient une épilepsie, facile à contrôler. Deux patients sont décédés (14%) à la suite d'infections respiratoires. Commentaire: Le MCD1A était le diagnostic principal dans le groupe de MCD, souvent plus élevé que celui qui est décrit dans la littérature; la présentation clinique et l'évolution a été la connue, mettant en évidence un pourcentage significatif avec l'épilepsie.
- Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific databasePublication . Oliveira, Jorge; Oliveira, Márcia E.; Kress, Wolfram; Taipa, Ricardo; Melo Pires, Manuel; Hilbert, Pascale; Baxter, Peter; Santos, Manuela; Buermans, Henk; den Dunnen, Johan; Santos, RosárioMyotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin – a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2–15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligation-dependent probe amplification (MLPA) analysis. A large duplication spanning exons 1–5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.
- Expanding the mutation spectrum of the MTM1 gene: the first multi-exonic duplication and establishment of the MTM1 locus-specific databasePublication . Oliveira, Jorge; Oliveira, Márcia E.; Brekelmans, Roel; Melo-Pires, Manuel; Guimarães, António; den Dunnen, Johan; Santos, Manuela; Santos, RosárioCentronuclear myopathies (CNM) are a group of diseases with variable onset and severity sharing as a distinctive histological feature, a high frequency of muscle fibers with centralized nuclei. Myotubular myopathy (MIM#310400) the X-linked form of CNM is characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin, a protein involved in myofiber differentiation and muscle cell architecture. In this work, eight patients were subjected to MTM1 MLPA analysis, selected according to the following criteria: (i) muscle biopsy compatible with CNM and (ii) exclusion of MTM1 point mutations by sequencing. We identified the first gross duplication spanning exons 1–5 (c.-76-?_342+?dup) in a 7 year old boy with progressive tetraparesis, ophtalmoparesis, facial diparesis and independent ambulation, the clinical course being milder than the classical myotubular myopathies. Analysis at the mRNA level revealed both normal transcripts and a mutated isoform lacking exon 6 (r.343_444del), suggesting somatic mosaicism. As suspected, this duplication was not detected in the patient’s mother. Considering the phenotypic expression in the patient, this mutational event most likely occurred de novo during early embryogenesis. We also describe the implementation of a locus-specific database (LSDB) for this gene using the Leiden Open Variation database (LOVD) software. The MTM1-LOVD (http://www.lovd.nl/MTM1) contains 372 mutation entries identified in 370 patients (last accessed March 2011). A total of 223 unique MTM1 mutations are listed in this LSDB, including: 207 point mutations, 15 single or multi-exonic deletions and the large duplication described in the present work. Despite the significant advances in this field during the last decade about one third of the CNM cases remain genetically unresolved. Here we show that gross MTM1 gene duplications may account for a fraction of these cases.
- Further contributions towards the molecular analysis of NIPBL and SMC1A genes in a cohort of patients with Cornelia de Lange SyndromePublication . Pinto da Costa, Eurico; Oliveira, Jorge; Silva, João; Santos, RosárioCornelia de Lange Syndrome [CdLS (MIM#122470)] is a rare multisystemic disorder, characterized by a typical phenotype that includes distinctive facial dysmorphism, hirsutism, growth and psychomotor developmental delay, abnormalities of the upper extremities, and relatively frequent gastrointestinal and congenital heart defects. CdLS is essentially caused by mutations in the NIPBL and SMC1A genes (~50% and 5% of cases, respectively), but mutations have been also described in other genes (PDS5A, PDS5B, SMC3) (http://www.lovd.nl/CDLS). This genetic heterogeneity in CdLS can however be explained by a close functional relationship at the cellular level, since all these proteins are involved in chromatid cohesion. The molecular and clinical characterization of 42 Portuguese CdLS patients has been previously described (Oliveira et al., 2010). In this work we conducted the molecular analysis of NIPBL gene and more recently expanded this study to other 20 patients. Subsequently, all the molecularly unresolved patients were screened for large deletions and duplications in NIPBL by MLPA, and point mutations in SMC1A by high resolution melting curve analysis and sequencing. Preliminary results allowed us to identify 4 previously known mutations (including a case with somatic mosaicism), 3 novel mutations (c.3316C>T, c.6983C>G and c.7307C>T) and 2 large deletions in the NIPBL gene. Mutation screening in SMC1A is still ongoing. Our results, at least for NIPBL gene analysis, suggest that the use of several different techniques is essential for attaining a high mutation detection rate. CdLS cases with somatic mosaicism are probably underestimated in the literature and may explain some degree of phenotypical variability.