RESUMO
INTRODUÇÃO: Em 5% a 6% dos IAM não são observadas lesões obstrutivas maiores que 50%, sendo estes classificados como MINOCA (Infarto do Miocárdio com Artérias Coronárias não Obstrutivas). Estudos maiores de longo prazo demonstraram que o prognóstico desses pacientes não é benigno com risco aumentado de morte e novos eventos cardiovasculares. MÉTODOS: Nesta coorte de centro único, todos os pacientes que preencheram os critérios diagnósticos para MINOCA com (1) IAM (2) ausência de estenose coronária ≥ 50% na artéria relacionada ao infarto e (3) nenhuma outra causa específica clinicamente evidente entre março de 2000 e junho de 2022 foram incluídos com um acompanhamento médio de 30 (9,5-67,3) meses. As características da amostra foram descritas em frequências e valores medianos (p25%-p75%). A incidência de um novo evento cardiovascular (CV) em 36 meses após a MINOCA foi estimada pelo método de Kaplan-Meier e o teste de log-rank aplicado para comparar os grupos, acompanhado de intervalos de confiança de 95% e alfa de 5% (R 3,6,1 para MacOS). RESULTADOS: Dos 126 pacientes, 57,1% eram mulheres com cerca de 50 anos de idade (42,0-57,8). 20,6% tinham diabetes, 47,6% dislipidemia, 60,3% hipertensão e 20% IAM prévio. A apresentação clínica predominante foi IAMSSST (55,6%) e 7 pacientes tiveram um episódio de morte súbita abortada durante a internação. 38,1% dos pacientes não tiveram uma etiologia identificada. O mecanismo fisiopatológico mais prevalente foi ruptura da placa < 50% (16,7%), seguido de tromboembolismo (13,5%) e dissecção espontânea de coronária (13,5%). Apenas 3,2% realizaram tomografia de coerência óptica (OCT) ou ultrassom intravascular (IVUS). Nenhum teste provocativo foi realizado. 44,4% realizaram ressonância magnética cardíaca (RMC), com mediana de tempo para realização de 180,0 (60,0-707,5) dias após o evento. Em relação à medicação prescrita na alta hospitalar, 79,4% tiveram betabloqueador e IECA/BRA prescritos, 14,3% iniciaram anticoagulação e apenas 34,1% receberam dupla antiagregação plaquetária (DAP). A incidência do desfecho composto (morte CV, novo IAM, AVC e internação CV) em 36 meses foi de 15% (IC95% 8,9%-24,6%). A incidência de novo IAM foi de 6,3% (N=8), de AVC 2,4% (N=3), de hospitalização CV 17,5% (N=22) e apenas um óbito. CONCLUSÃO: Chama a atenção o risco do desfecho primário em 36 meses. Notavelmente, a maior parte da incidência foi atribuída à hospitalização CV. Um número importante de pacientes recebeu alta sem etiologia conhecida para sua apresentação clínica e, consequentemente, sem tratamento individualizado.
RESUMO
Duchenne muscular dystrophy (DMD), a severe and lethal condition, is caused by the absence of muscle dystrophin. Therapeutic trials aiming at the amelioration of muscle function have been targeting the production of muscle dystrophin in affected Duchenne patients. However, how much dystrophin is required to rescue the DMD phenotype remains an open question. We have previously identified two exceptional golden retriever muscular dystrophy (GRMD) dogs with a milder course despite the total absence of muscle dystrophin. Here we report two unusual patients carrying nonsense mutations in the DMD gene and dystrophin deficiency but with an unexpectedly mild phenotype. Three reported polymorphisms, respectively in genes LTBP4, SPP1 and ACTN3 were excluded as possible DMD genetic modifiers in our patients. Finding the mechanisms that protect some rare patients and dogs from the deleterious effect of absent muscle dystrophin is of utmost importance and may lead to new avenues for treatment. Importantly, these observations indicate that it is possible to have a functional large muscle even without dystrophin.
Assuntos
Códon sem Sentido/genética , Distrofina/genética , Distrofia Muscular de Duchenne/genética , Actinas/genética , Adolescente , Feminino , Humanos , Proteínas de Ligação a TGF-beta Latente/genética , MasculinoRESUMO
The most frequent inherited peripheral neuropathy is the peripheral myelin protein 22 (PMP22) gene related disease. Duplication, deletion, and point mutations in that gene are associated with phenotypic variability. Here we report a family carrying a novel mutation in the PMP22 gene (c. 327C>A), which results in a premature stop codon (Cys109stop). The family members who carry this mutation have a Charcot-Marie-Tooth type 1 variable phenotype, ranging from asymptomatic to severely affected. These findings suggest that the fourth transmembrane domain of the PMP22 gene may play an important role, although the intrafamilial clinical variability reinforces the observation that pathogenic mutations are not always phenotype determinant and that other factors (genetic or epigenetic) modulate the severity of the clinical course.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Códon de Terminação/genética , Mutação , Proteínas da Mielina/genética , Fenótipo , Adolescente , Adulto , Idoso , Axônios/patologia , Axônios/ultraestrutura , Biópsia/métodos , Doença de Charcot-Marie-Tooth/fisiopatologia , Cisteína/genética , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Humanos , Masculino , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Exame Neurológico/métodos , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Nervo Sural/patologia , Nervo Sural/ultraestruturaRESUMO
Facioscapulohumeral muscular dystrophy is an autosomal dominant muscle disorder, mapped to 4q35. It is characterized by remarkable inter- and intrafamilial clinical variability ranging from severe phenotype to asymptomatic carriers. The aim of the present study was to assess the size of the Eco RI fragment in a large sample of asymptomatic or minimally affected carriers as well as symptomatic patients, comparing both sexes, in order to verify if asymptomatic carriers are randomly distributed or concentrated in some particular families and if there is preferential parental transmission (maternal or paternal) resulting in non-penetrant carriers. We have analysed a total of 506 individuals from 106 unrelated families with at least one affected facioscapulohumeral muscular dystrophy proband. In all patients the molecular diagnosis was confirmed following double digestion (Eco RI/Bln I fragment <35 kb). About 20% among probands' relatives who were found to carry the small fragment were asymptomatic or minimally affected, without preferential parental transmission, but with a significantly higher proportion of females (n=37) than males (n=14). Although asymptomatic carriers were found in about 30% of the families, some genealogies seem to concentrate more non-penetrant cases. A significant correlation between the size of the Eco RI fragment and severity of the phenotype was observed in the total sample but surprisingly this correlation is significant only among affected females. The gender difference in clinical manifestation as well as the observation that asymptomatic carriers are not rare should be taken into consideration in genetic counseling of affected patients or 'at-risk' relatives.
Assuntos
Desoxirribonuclease EcoRI/genética , Heterozigoto , Distrofia Muscular Facioescapuloumeral/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Peso Molecular , Penetrância , Fenótipo , Fatores de Risco , Fatores SexuaisAssuntos
Proteínas do Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adolescente , Adulto , Brasil , Criança , Pré-Escolar , Proteínas do Citoesqueleto/metabolismo , Distroglicanas , Distrofina/genética , Distrofina/metabolismo , Saúde da Família , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Mutação , Fenótipo , SarcoglicanasRESUMO
The BCL3 gene has been considered a susceptibility locus for nonsyndromic cleft lip with or without cleft palate (NSCL/P), based on association and linkage studies in some populations. We evaluated an intragenic marker at the BCL3 gene and the microsatellite D19S178 (1.1 cM distant from the BCL3 gene) among 98 infants born with NSCL/P and their parents, using the transmission disequilibrium test (TDT) and a method for haplotype analysis. Our analysis, based on BCL3 alleles, revealed the existence of a marginal association of allele 135pb of the BCL3 gene with NSCL/P (chi(2)=3.60; P=0.058; 1 df), with a major effect in female (chi(2)=5.77; P=0.016; 1 df) and in familial cases (chi(2)=3.79; P=0.051; 1 df). However, the haplotype analysis detected no significant segregation distortion, even if the alleles of the D19S178 were grouped into two classes. These findings support previous findings that BCL3 plays a role in the etiology of NSCL/P as an allele of low penetrance or as a modifier locus. We hypothesize that there might be more than one mutation in this gene associated with NSCL/P, or alternatively, that more than one mutation has arisen associated with the 135-bp allele. Genet. Epidemiol. 23:364-374, 2002
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Ligação Genética , Proteínas Proto-Oncogênicas/genética , Alelos , Proteína 3 do Linfoma de Células B , Brasil/epidemiologia , Distribuição de Qui-Quadrado , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , DNA/análise , Feminino , Genótipo , Haplótipos , Humanos , Recém-Nascido , Escore Lod , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Fatores de TranscriçãoRESUMO
We report on two unrelated Brazilian families with members affected by two different forms of muscular dystrophy. In the first one, the 35-year-old male proband has limb-girdle muscular dystrophy with proximal weakness, elevated creatine kinase and a myopathic muscle biopsy. All the proteins known to be associated with limb-girdle muscular dystrophy were normal. Two of his sisters also complained of muscle weakness. The oldest sister showed clinical signs consistent with facioscapulohumeral muscular dystrophy, confirmed through molecular analysis. She presented a 30 kb EcoRI/BlnI fragment which was found in another six relatives, but surprisingly not in the affected proband or the other sister. In the second family, a 57-year-old male with a typical facioscapulohumeral muscular dystrophy phenotype has a 17 kb EcoRI/BlnI fragment, which was also present in other affected relatives. However in a 14-year-old severely affected male cousin, confined to a wheelchair since age 12, but without facial weakness, the small fragment was absent. These families illustrate the importance of testing all affected individuals in a family.
Assuntos
Distrofias Musculares/genética , Distrofia Muscular Facioescapuloumeral/genética , Adolescente , Adulto , Biópsia , Brasil , Aberrações Cromossômicas , Eletromiografia , Eletroforese em Gel de Campo Pulsado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Distrofias Musculares/fisiopatologia , Distrofia Muscular Facioescapuloumeral/fisiopatologia , Linhagem , FenótipoRESUMO
Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D, 2E and 2F). The other five forms, usually causing a milder phenotype are LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2G (telethonin), LGMD2H (9q31-11), and LGMD21 (19q13.3). We studied dysferlin expression in a total of 176 patients, from 166 LGMD families: 12 LGMD2B patients, 70 with other known forms of muscular dystrophies (LGMD2A, sarcoglycanopathies, LGMD2G), in an attempt to assess the effect of the primary gene-product deficiency on dysferlin. In addition, 94 still unclassified LGMD families were screened for dysferlin deficiency. In eight LGMD2B patients from five families, no dysferlin was observed in muscle biopsies, both through immunofluorescence (IF) and Western blot methodologies, while in two families, a very faint band was detected. Both patterns, negative or very faint bands, were concordant in patients belonging to the same families, suggesting that dysferlin deficiency is specific to LGMD2B. Myoferlin, the newly identified homologue of dysferlin was studied for the first time in LGMD2B patients. Since no difference was observed between patients mildly and severely affected, this protein do not seem to modify the phenotype in the present dysferlin-deficient patients. Dystrophin, sarcoglycans, and telethonin were normal in all LGMD2B patients, while patients with sarcoglycanopathies (2C, 2D, and 2E), LGMD2A, LGMD2G, and DMD showed the presence of a normal dysferlin band by Western blot and a positive pattern on IF. These data suggest that there is no interaction between dysferlin and these proteins. However, calpain analysis showed a weaker band in four patients from two families with intra-familial concordance. Therefore, this secondary deficiency of calpain in LGMD2B families, may indicate an interaction between dysferlin and calpain in muscle. Dysferlin was also present in cultured myotubes, in chorionic villus, and in the skin. Dysferlin deficiency was found in 24 out of a total of 166 Brazilian AR-LGMD families screened for muscle proteins (approximately 14%), thus representing the second most frequent known LGMD form, after calpainopathy, in our population.
Assuntos
Proteínas de Membrana , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiopatologia , Distrofias Musculares/metabolismo , Adulto , Idade de Início , Proteínas de Ligação ao Cálcio , Calpaína/genética , Calpaína/metabolismo , Criança , Conectina , Disferlina , Distrofina/genética , Distrofina/metabolismo , Feminino , Ligação Genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Mutação , Polissacarídeos/genética , Polissacarídeos/metabolismoRESUMO
In patients with sarcoglycan (SG) deficiency, a primary defect in any one of the four SG proteins usually leads to reduced expression of the whole SG complex. We report a limb-girdle muscular dystrophy type 2D family (LGMD2D), with variable phenotype, where a mutation in the alpha-SG gene resulted in the partial deficiency of alpha-SG alone. The normal expression of the other three SG proteins suggests that mutations close to the alpha-SG transmembrane domain might be less critical for complex integrity, and that weakness may occur despite its retention.
Assuntos
Proteínas do Citoesqueleto/genética , Distrofina/genética , Saúde da Família , Glicoproteínas/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adulto , Biópsia , Distrofina/análise , Glicoproteínas/análise , Humanos , Masculino , Músculo Esquelético/química , Músculo Esquelético/patologia , Distrofias Musculares/patologia , Mutação , Núcleo Familiar , Linhagem , Polimorfismo Conformacional de Fita Simples , SarcoglicanasAssuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Polimorfismo Genético/genética , Brasil , Estudos de Casos e Controles , Etnicidade , Feminino , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Classe Social , SíndromeRESUMO
The aim of the present study was to assess the impact of genetic counseling in young women at risk to have Duchenne muscular dystrophy (DMD) children prior to childbearing. A total of 263 potential DMD carriers, who had had genetic counseling and were given different genetic risks, were included in this investigation. Their reproductive outcome and future plans as well as their requests for DNA tests (for carrier detection and prenatal diagnosis) were analyzed according to genetic risk magnitude, comprehension of genetic counseling is- sues, family and personal history, socio-educational level, and subjective opinion about selective abortion. We noted that genetic risk magnitude had no significant influence on reproductive plans or outcome nor on the request for additional DNA testing, even considering only those clients with good comprehension and retention of issues discussed during genetic counseling. On the other hand, counselees who had more than one affected or at least one deceased DMD case in their family understood genetic counseling significantly better, suggesting that "learning with life" has a stronger impact than genetic counseling.
Assuntos
Serviços de Planejamento Familiar , Aconselhamento Genético , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/genética , Paridade , Adulto , Atitude Frente a Saúde , DNA/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Humanos , Diagnóstico Pré-Natal , Fatores de RiscoRESUMO
van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.
Assuntos
Cromossomos Humanos Par 17/genética , Fissura Palatina/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Anormalidades Múltiplas , Brasil , Cromossomos Humanos Par 1/genética , Saúde da Família , Feminino , Marcadores Genéticos/genética , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Penetrância , Fenótipo , SíndromeRESUMO
Sarcoglycanopathies (SGPs) constitute a subgroup of limb-girdle muscular dystrophies (LGMD), where the primary defect in one sarcoglycan (SG) glycoprotein (alpha-SG, beta-SG, gamma-SG or delta-SG) results in a deficiency of the whole complex. Four genes, at 17q, 4q, 13q and 5q, encode the four glycoproteins, and mutations in these genes cause diseases called LGMD2D, 2E, 2C and 2F. To estimate the prevalence, relative proportions and clinical features of SGPs, we have studied the SG proteins in muscle biopsies of 140 patients (from 115 unrelated Brazilian families) with a clinical diagnosis of LGMD. Alpha-SG immunofluorescence analysis showed a positive staining pattern in 70% (80/115) of the families, a patchy pattern in 14% (16/115) and a negative pattern in 16% (19/115) of the families. All the 19 alpha-SG negative, and four of the 16 alpha-SG patchy patients were also deficient for the other three SG proteins, confirming the diagnosis of SGP in 20% of the LGMD families. None of the positive alpha-SG patients were deficient for any of the other three SG proteins, supporting the view that the SG complex functions as a unit. DNA analysis for the four sarcoglycan genes showed that alpha-SG mutations accounted for 47%, beta-SG for 16%, gamma-SG for 16% and delta-SG for 21% of the cases. SG abnormalities were observed in only 8.5% of patients with milder LGMD forms, but were present in 68% of patients with a severe Duchenne-like course. The relatively high frequency of SGP among Brazilian people with LGMD may be due to the disproportionally high frequency of African Brazilian SGP patients with the same mutation (particularly among LGMD2C and 2F patients), suggesting a founder effect. Consanguinity is also common in our SGP families.
Assuntos
Proteínas do Citoesqueleto/genética , Distrofias Musculares/genética , Adolescente , Adulto , Brasil/epidemiologia , Criança , Proteínas do Citoesqueleto/análise , Análise Mutacional de DNA , Distroglicanas , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Músculo Esquelético/química , Distrofias Musculares/diagnóstico , Distrofias Musculares/epidemiologia , SarcoglicanasRESUMO
We investigated 52 families of patients with facioscapulohumeral muscular dystrophy (FSHD1), including 172 patients (104 males and 68 females). Among 273 DNA samples which were analyzed with probe p13E-11, 131 (67 males and 64 females) were shown to carry an EcoRI fragment smaller than 35 kb; 114 among them were examined clinically and neurologically. Results of the present investigation showed that: a) there is no molecular evidence for autosomal or X-linked recessive inheritance of FSHD1; b) an excess of affected males, which is explained by a significantly greater proportion of females than males among asymptomatic cases and a significantly greater proportion of affected sons than daughters observed in the offspring of asymptomatic mothers; c) the penetrance of the FSHD1 gene until age 30 was estimated as 83% for both sexes but was significantly greater for males (95%) than for females (69%); d) new mutations occur significantly more frequently in females than males among somatic/germinal mosaic cases; and e) severely affected cases originated more often through new mutations or were transmitted through maternal than through paternal lines including somatic/germinal mothers. These observations have important implications for understanding the molecular mechanisms responsible for FSHD1 and for genetic and prognostic counseling according to the gender of the affected patient.
Assuntos
Distrofias Musculares/genética , Penetrância , Proteínas/genética , Adolescente , Adulto , Criança , Desoxirribonuclease EcoRI , Feminino , Genes Dominantes , Genes Recessivos , Heterozigoto , Humanos , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Mosaicismo/genética , Mutação , Proteínas Nucleares , Linhagem , Fenótipo , Polimorfismo de Fragmento de Restrição , Proteínas de Ligação a RNA , Deleção de Sequência , Fatores SexuaisRESUMO
Duchenne (DMD) and Becker (BMD) type muscular dystrophies are allelic X-linked recessive disorders caused by mutations in the gene encoding dystrophin. About 65% of the cases are caused by deletions, while 5-10% are duplications. The remaining 30% of affected individuals may have smaller mutations (point mutations or small deletions/insertions) which cannot be identified by current diagnostic screening strategies. In order to look for pathogenic small mutations in the dystrophin gene, we have screened the 18 exons located in the hot spot region of this gene through two different single strand conformation polymorphism (SSCP) conditions. Five different pathogenic mutations were identified in 6 out of 192 DMD/BMD patients without detectable deletions: 2 nonsense, 1 bp insertion, 1 bp deletion and 1 intronic. Except for the intronic change, which alters a splice site, all the others cause a premature stop codon. In addition, 8 apparently neutral changes were identified. However, interestingly, one of them was not identified in 195 normal chromosomes, although it was previously described in a DMD patient from a different population. The possibility that this mutation may be pathogenic is discussed. Except for two neutral changes, all the others are apparently here described for the first time.
Assuntos
Distrofina/genética , Mutação Puntual , Distrofina/química , Deleção de Genes , Testes Genéticos , Humanos , Masculino , Distrofias Musculares/etiologia , Distrofias Musculares/genética , Polimorfismo Genético , Polimorfismo Conformacional de Fita SimplesRESUMO
Autosomal recessive limb-girdle muscular dystrophies (LGMDs) are genetically heterogeneous. A subgroup of these disorders is caused by mutations in the dystrophin-associated sarcoglycan complex. Truncating mutations in the 43 kDa beta-sarcoglycan gene (LGMD 2E) were originally identified in a sporadic case of Duchenne-like muscular dystrophy, and a common missense mutation (T151R) was identified independently in Indiana Amish pedigrees with a milder form of LGMD. To facilitate mutational analysis of larger numbers of patients directly from genomic DNA, as opposed to reverse transcribed RNA from muscle biopsies, we have determined the genomic structure of the beta-sarcoglycan gene. The open reading frame of the beta-sarcoglycan coding region extends over six exons. Primers were designed for PCR amplification of single exons from genomic DNA and subsequent single strand conformation polymorphism (SSCP) analysis. We screened 15 patients from the Brazilian LGMD patient population, 13 of whom followed a severe course. Most of the patients had been assessed previously for deficiency of alpha-sarcoglycan immunofluorescence on muscle biopsy sections as a marker for disease of the sarcoglycan complex. Novel mutations in two familial and two sporadic cases of severe childhood-onset LGMD were identified. Only one of these patients carried a truncating mutation (homozygous 2 bp deletion, FS164TER), while the other three carried missense mutations (homozygous R91P, homozygous M100K, heterozygous recessive L108R; only one allele could be identified in this family). All three missense mutations occurred in exon 3, coding for the immediate extracellular domain. Complete absence for all three of the known sarcoglycans was noted by immunohistochemistry on muscle biopsy sections of the patients.
Assuntos
Proteínas do Citoesqueleto/genética , Genoma Humano , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Sequência de Aminoácidos , Sequência de Bases , Distroglicanas , Éxons/genética , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Polimorfismo GenéticoRESUMO
To enhance our understanding of the autosomal recessive limb-girdle muscular dystrophy (LGMD), patients from six genetically distinct forms (LGMD2A to LGMD2F) were studied with antibodies directed against four sarcoglycan subunits (alpha-, beta-, gamma-, delta-SG), dystrophin, beta-dystroglycan (beta-DG) and merosin. All patients with LGMD2A and 2B had a mild clinical course while those with a primary sarcoglycan mutation (LGMD2C to 2F) had a range of clinical severity. Dystrophin and merosin immunofluorescence pattern was positive in patients with all six AR LGMDs. The majority of patients with a severe Duchenne-like phenotype presented total absence of the SG complex. However, some exceptions were found in 13q linked patients, indicating that the presence of a certain labelling for components of the SG may not be prognostic for a milder phenotype. The observation that the primary absence of alpha-SG results in the total absence of beta- and delta-SG but not of gamma-SG suggests that the alpha-, beta- and delta-subunits of sarcoglycan may be more closely associated. A secondary reduction in dystrophin amount was seen in patients with primary sarcoglycan mutations, which was most marked in patients with primary beta-, gamma- and delta-SG deficiencies. In contrast, beta-DG staining was retained in all patients, suggesting that the association between SG and DG subcomplexes is not so strong. Based on the above findings, we have refined the model for the interaction among the known glycoproteins of the sarcoglycan complex, within the DGC.