RESUMO
Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. Several genomic screens have suggested that a region between chromosome 12p13 and 12q22 contains at least one additional locus underlying the susceptibility of AD. However, localization of this locus has been difficult. We performed a 5 cM microsatellite marker screen across 74 cM on chromosome 12 with 15 markers in 585 multiplex families consisting of 994 affected sibpairs and 213 other affected relative pairs. Analyses across the entire data set did not reveal significant evidence of linkage. However, suggestive linkage was observed in several subsets. In the 91 families where no affected individuals carry an ApoE varepsilon4 allele, an HLOD score of 1.55 was generated at D12S1042. We further examined the linkage data considering the proposed linkages to chromosome 9 (D9S741) and chromosome 10 (alpha-catenin gene). There was a modest (P=0.20) increase in the LOD score for D12S368 (MLOD=1.70) when using the D9S741 LOD scores as a covariate and a highly significant (P<0.001) increase in the MLOD score (4.19) for D12S1701 in autopsy-confirmed families (n=228) when using alpha-catenin LOD scores as a covariate. In both cases, families with no evidence of linkage to D9S741 or alpha-catenin demonstrated most of the evidence of linkage to chromosome 12, suggesting locus heterogeneity. Taken together, our data suggest that the 16 cM region between D12S1042 and D12S368 should be the subject of further detailed genomic efforts for the disease.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 12 , Idade de Início , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 9 , Família , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , IrmãosRESUMO
Hereditary benign intraepithelial dyskeratosis (HBID) is an autosomal dominant disorder characterized by elevated epithelial plaques on the ocular and oral mucous membranes. It has been reported primarily, but not exclusively, in individuals of American Indian heritage in North Carolina. We have examined and obtained DNA on two large families affected by HBID. Using genetic linkage analysis we have localized the HBID gene to chromosome 4 (4q35) with a peak LOD score of 8.97. Molecular analysis of these data reveals that all individuals affected with HBID in both families demonstrate the presence of three alleles for two tightly linked markers, D4S1652 and D4S2390, which map to the telomeric region of 4q35. This suggests the presence of a duplication segregating with the disease phenotype that is most likely involved in its causation.
Assuntos
Aberrações Cromossômicas/genética , Cromossomos Humanos Par 4/genética , Doenças da Túnica Conjuntiva/genética , Duplicação Gênica , Alelos , Doenças da Túnica Conjuntiva/patologia , DNA/genética , Saúde da Família , Feminino , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Linhagem , PenetrânciaRESUMO
BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the underlying pathologic entity in 5% of adults and 20% of children with end-stage renal disease (ESRD). FSGS is generally considered to be sporadic in origin. METHODS: Recently, we identified 60 families involving 190 individuals with familial FSGS, providing evidence for a subset of families in which a genetic form is segregating. Each family had at least one member with renal biopsy-confirmed FSGS and at least one other member with either renal biopsy-confirmed FSGS or ESRD. RESULTS: Twenty-six families had individuals affected in more than one generation [multigeneration (MG)], and the remaining 34 families had only a single generation (SG) affected. There was equal representation of males and females among affected individuals. Ten percent of MG families were African American, and 52% of SG families were African American. The mean age of presentation was significantly higher in the MG families (32.5 +/- 14.6 years) compared with the SG families (20.1 +/- 12.1 years, P = 0.0001). SG cases had higher levels of proteinuria at presentation (7.0 +/- 5.6 g/24 hr, compared with 3.8 +/- 3.4 g/24 hr, for the MG families, P = 0.002). On renal biopsy, tubulointerstitial damage was more severe in patients in the SG families than in the MG families; however, the level of glomerular damage did not differ between these groups. Fifty percent of the patients had progressed to ESRD by the age of 30 years. Variables measured at presentation that were independently associated with poor renal survival were decreased age, increased serum creatinine, and increased urinary protein excretion. Forty-one patients underwent successful renal transplantation, with a 10-year graft survival rate of 62%. One patient developed clinical and biopsy evidence of recurrence of FSGS in the allograft. CONCLUSION: These data confirm the existence of a non-Alport's form of hereditary glomerulonephritis, which has a morphological pattern of FSGS.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Adulto , Idoso , Feminino , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Falência Renal Crônica/etiologia , Transplante de Rim , Masculino , Pessoa de Meia-IdadeRESUMO
Focal segmental glomerulosclerosis (FSGS) is a pathological entity characterized by proteinuria, nephrotic syndrome, and the progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD). Recently, familial forms of FSGS have been identified. Two families with autosomal dominant FSGS were evaluated for linkage using 351 genomic microsatellite markers. Linkage, multipoint analysis, and tests for heterogeneity were performed on the subsequent results. In addition, three small families were used for haplotype analysis. Evidence for linkage was found on chromosome 11q21-q22 for the largest family, with a maximum lod score of 9.89. The gene is currently localized to an 18-cM area between flanking markers D11S2002 and D11S1986. The disease in a second family was not linked to this locus or to a previously described locus on chromosome 19q13. There were no shared haplotypes among affected individuals in the three smaller families. Our findings demonstrate that genetic heterogeneity is prevalent in FSGS in that at least three genes cause the FSGS phenotype. Identification of the genes that cause familial FSGS will provide valuable insights into the molecular basis and pathophysiology of FSGS.
Assuntos
Cromossomos Humanos Par 11 , Heterogeneidade Genética , Ligação Genética , Glomerulosclerose Segmentar e Focal/genética , Adolescente , Adulto , Idade de Início , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Rim/anatomia & histologia , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Familial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530). METHODS: Families were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test. RESULTS: Linkage was excluded at a distance of +/- 5 to 10 CM for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60 CM interval in this area of chromosome 19q via multipoint analysis. CONCLUSIONS: FSGS has been called the "final common pathway" of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Adolescente , Adulto , Cromossomos Humanos Par 19/genética , Feminino , Genes Dominantes , Heterogeneidade Genética , Ligação Genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
The presence of antibody to the chromosomal centromere appears to be associated with a subset of patients with the limited CREST form of scleroderma. To further define the prognostic value of this autoantibody, 27 patients, who were identified as having anticentromere antibody by screening antinuclear antibody tests using HEp-2 cell substrates, were followed clinically and serologically for 2 years. The presence of anticentromere antibody is common in the limited CREST forms of systemic sclerosis, and it is often the only autoantibody specificity present in the sera of patients with the CREST variant. When compared with other patients who exhibit speckled or nucleolar antinuclear antibody patterns, those with anticentromere antibody had significantly less major organ system involvement.
Assuntos
Anticorpos Antinucleares/imunologia , Centrômero/imunologia , Cromossomos/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Calcinose/imunologia , Doenças do Esôfago/imunologia , Feminino , Imunofluorescência , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença de Raynaud/imunologia , Síndrome , Telangiectasia/imunologiaRESUMO
Antibodies to components of the cell nucleus have been viewed as specific serological markers of systemic lupus erythematosus (SLE). To determine whether these autoantibodies exhibit common regulation of their expression, antibody levels have been quantitatively assessed in serial samples from patients producing at least 2 different antibody specificities. In a comparison of the peak antibody levels as a measure of immune responsiveness, the magnitude of the antiDNA response varied independently of either the antiSm or the antiRNP responses. Serial analysis with selected patients demonstrated that antiDNA levels fluctuated according to a pattern related to disease activity. In the same patients, however, antiSm and antiRNP antibodies showed little variation in level, with no consistent relationship to disease activity. Furthermore, following therapy, antiDNA levels fell while neither antiSm nor antiRNP levels showed significant alteration. These results suggest that in SLE, autoantibodies may arise from distinct immunoregulatory disturbances, each characterized by a unique relationship to disease activity and response to therapy.