RESUMO
Contractions in the polymorphic D4Z4 repeat array of subtelomere 4qter cause autosomal dominant facioscapulohumeral muscular dystrophy in humans. A polymorphic segment of 10 kb directly distal to D4Z4 exists in two allelic forms, 4qA and 4qB. Although both alleles are equally common in the general population, we now report that FSHD is associated solely with the 4qA allele.
Assuntos
Cromossomos Humanos Par 4 , Distrofia Muscular Facioescapuloumeral/genética , Polimorfismo Genético , Feminino , Humanos , Masculino , Linhagem , Sequências Repetitivas de Ácido Nucleico , TelômeroRESUMO
The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show that this contraction causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results strongly suggest that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1.
Assuntos
Cromossomos Humanos Par 4/genética , Metilação de DNA , Distrofia Muscular Facioescapuloumeral/genética , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico/genética , Feminino , Genótipo , Humanos , Masculino , LinhagemRESUMO
Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G). Eight relatives were homozygous for both polymorphisms, which occurred in only approximately 7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS.
Assuntos
Arritmias Cardíacas/genética , Função Atrial/genética , Conexinas/genética , Mutação , Canais de Sódio/genética , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Análise Mutacional de DNA , Tontura/etiologia , Eletrocardiografia , Feminino , Genótipo , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5 , Países Baixos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Polimorfismo Genético , Canais de Sódio/metabolismo , Síncope/etiologia , Transfecção , Xenopus laevis , Proteína alfa-5 de Junções ComunicantesRESUMO
Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24.
Assuntos
Diabetes Mellitus Tipo 1/genética , Desequilíbrio de Ligação , Alelos , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 8 , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Países Baixos , LinhagemRESUMO
Multiple genes, interacting with the environment, contribute to the susceptibility to type 2 diabetes. We performed a genome-wide search to localize type 2 diabetes susceptibility genes in a recently genetically isolated population in the Netherlands. We identified 79 nuclear families with type 2 diabetes who were related within 13 generations and performed a 770-marker genome-wide scan search for shared founder alleles. Twenty-six markers yielded a logarithm of odds (LOD) score >0.59 (nominal P < 0.05), of which 7 reached LOD scores >1.17 (nominal P < 0.01). The strongest evidence for a type 2 diabetes locus was at marker D18S63 on chromosome 18p (LOD 2.3, P = 0.0006). This region was investigated further using additional markers. For one of these markers (D18S1105), we found a significant association with type 2 diabetes (odds ratio 6.7 [95% CI 1.5-30.7], P = 0.005 for the 97-bp allele, assuming a dominant model), which increased when limiting the analysis to patients with high BMI (12.25 [2.1-71], P = 0.003). A locus on chromosome 18p in patients with high BMI was suggested earlier by Parker et al. Our study is the first to confirm this locus.
Assuntos
Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Genoma Humano , Alelos , Índice de Massa Corporal , Mapeamento Cromossômico , Cromossomos Humanos Par 18/genética , Demografia , Diabetes Mellitus Tipo 2/patologia , Efeito Fundador , Genes Dominantes , Marcadores Genéticos , Predisposição Genética para Doença/genética , Humanos , Escore Lod , Pessoa de Meia-Idade , Países BaixosRESUMO
A re-emerging strategy in the search for disease susceptibility genes is the evaluation of candidate genes, which are thought to play a role in disease pathogenesis. Candidate genes are screened for single nucleotide polymorphisms (SNPs) in a case-control study. The factor V Leiden (FVL) mutation (1691G --> A in the F5 gene) is an important risk factor for venous thrombosis. We asked ourselves whether the FVL mutation would have been found using the candidate gene approach in the absence of prior knowledge of the haplotype structure of the F5 gene. We typed four SNPs in the F5 gene in the Leiden Thrombophilia study, that is, promoter (99930G --> A), exon 13 (55907A --> G), exon 16 (42855A --> G), and intron 19 (37833T --> G). These SNPs were known to have different population frequencies, making their presence in distinct haplotypes likely. None of these SNPs has previously been associated with venous thrombotic risk. Subsequently we derived haplotypes. One haplotype was clearly more frequent in patients than controls (GAAT; 20 versus 9%), suggesting that a polymorphism in or near the F5 gene in this haplotype is associated with an increased thrombotic risk. If we had sequenced the F5 gene in patients homozygous for this haplotype, in order to locate the possible causal polymorphism, we would have found that 16 (76%) patients were homozygous or heterozygous for a missense mutation in exon 10 (1691G --> A), which predicts the replacement of Arg506 by Gln in one of the cleavage sites for activated protein C, a mutation that we now know as the FVL mutation.
Assuntos
Fator V/genética , Predisposição Genética para Doença/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Trombofilia/genética , Trombose Venosa/genética , Estudos de Casos e Controles , Frequência do Gene , Genética Populacional , Humanos , Fatores de RiscoRESUMO
Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.
Assuntos
Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença , Haplótipos , Esclerose Múltipla/genética , Feminino , Testes Genéticos , Humanos , Desequilíbrio de Ligação , Masculino , LinhagemRESUMO
The design and feasibility of genetic studies of complex diseases are critically dependent on the extent and distribution of linkage disequilibrium (LD) across the genome and between different populations. We have examined genomewide and region-specific LD in a young genetically isolated population identified in the Netherlands by genotyping approximately 800 Short Tandem Repeat markers distributed genomewide across 58 individuals. Several regions were analyzed further using a denser marker map. The permutation-corrected measure of LD was used for analysis. A significant (P<0.0004) relation between LD and genetic distance on a genomewide scale was found. Distance explained 4% of the total LD variation. For fine-mapping data, distance accounted for a larger proportion of LD variation (up to 39%). A notable similarity in the genomewide distribution of LD was revealed between this population and other young genetically isolated populations from Micronesia and Costa Rica. Our study population and experiment was simulated in silico to confirm our knowledge of the history of the population. High agreement was observed between results of analysis of simulated and empirical data. We conclude that our population shows a high level of LD similar to that demonstrated previously in other young genetic isolates. In Europe, there may be a large number of young genetically isolated populations that are similar in history to ours. In these populations, a similar degree of LD is expected and thus they may be effectively used for linkage or LD mapping.
Assuntos
Genética Populacional , Desequilíbrio de Ligação/genética , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Repetições Minissatélites/genética , Países Baixos , População Branca/genéticaRESUMO
More insight into the differential immunogenicity of human leukocyte antigen (HLA) mismatches will be beneficial for donor selection in clinical transplantation. In this study the immunogenicity of HLA antigens was analyzed by examining the antibody profiles in women who have been pregnant. In total 888 women, who had pregnancy induced HLA alloantibodies, were included in this study, while 413 women who had not been immunized by their pregnancy, served as controls. First it was analyzed whether women expressing particular HLA antigens are more likely to produce HLA alloantibodies. Next we determined whether certain HLA mismatches of their children are more immunogenic than other ones. Finally we studied whether the immunogenicity of specific HLA mismatches is dependent on the HLA phenotype of the women. Women expressing HLA-A3, HLA-A32, and HLA-B21 are more likely to produce alloantibodies whereas women expressing HLA-B13 and HLA-B17 have a significantly lower incidence of alloantibodies compared with women expressing other HLA antigens. Children with HLA-A2 or HLA-B5 mismatches induced alloantibodies significantly more often whereas children with HLA-A30, -A31 or -A33 and HLA-A28 induced alloantibodies significantly less often than children with other HLA class I mismatches. Finally we could demonstrate that the immunogenicity of a particular HLA mismatch is dependent on the HLA phenotype of the women. Information on the differential immunogenicity of HLA mismatches may be of benefit for the determination of acceptable and taboo mismatches in the case of donor selection for (highly sensitized) patients.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Isoanticorpos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Fenótipo , GravidezRESUMO
OBJECTIVES: To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1]). METHODS: Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1. RESULTS: Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centromeric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta = 0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms. CONCLUSIONS: A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 22/genética , Oftalmopatias Hereditárias/genética , Degeneração Retiniana/genética , Corpo Vítreo/patologia , Idoso , Sequência de Bases , Análise Mutacional de DNA , Proteínas da Matriz Extracelular/genética , Oftalmopatias Hereditárias/patologia , Feminino , Genes Recessivos , Haplótipos , Homozigoto , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Biologia Molecular , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Degeneração Retiniana/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive-compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.
Assuntos
Deriva Genética , Transtornos Mentais/epidemiologia , Modelos Genéticos , Isolamento Social , Atitude Frente a Saúde , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Cromossomos Humanos/genética , Costa Rica/epidemiologia , Humanos , Indígenas Centro-Americanos/genética , Transtornos Mentais/genética , Preconceito , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Espanha/etnologia , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/genéticaRESUMO
OBJECTIVE: To determine whether preeclampsia is either associated with or linked to two polymorphisms in the IL1B gene (IL1B-TaqI and IL1B-511) and one polymorphism in the IL1RN gene (IL1RN-IVS2). METHODS: Genotyping was performed in 150 affected sib-pair families and 104 healthy Dutch blood donors. Genotype and allele frequencies as well as allelic associations were assessed in three groups of unrelated women from these 150 families; 133 with either eclampsia, preeclampsia or the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, 101 with preeclampsia only, and 63 with HELLP syndrome only. These frequencies were compared to those in controls. Frequencies of transmitted and nontransmitted haplotypes, inferred from the three polymorphisms, were compared. Allele sharing between affected siblings from all 150 families was assessed by means of multipoint nonparametric affected sib-pair analyses. RESULTS: No significant differences in genotype and allele frequencies were found between the unrelated study groups and controls. No allelic associations were apparent, nor were there differences in frequencies of transmitted and nontransmitted haplotypes within affected families. Excess allele sharing for any of the three polymorphic markers was absent in affected sib-pairs. CONCLUSIONS: None of the IL1B and IL1RN polymorphisms provided evidence for either association or linkage with the risk for (pre)eclampsia/HELLP syndrome, preeclampsia only or HELLP syndrome only.
Assuntos
Ligação Genética/genética , Síndrome HELLP/genética , Interleucina-1/genética , Pré-Eclâmpsia/genética , Receptores de Interleucina-1/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo Genético , GravidezRESUMO
We have ascertained in the Central Valley of Costa Rica a new kindred (CR201) segregating for severe bipolar disorder (BP-I). The family was identified by tracing genealogical connections among eight persons initially independently ascertained for a genome wide association study of BP-I. For the genome screen in CR201, we trimmed the family down to 168 persons (82 of whom are genotyped), containing 25 individuals with a best-estimate diagnosis of BP-I. A total of 4,690 SNP markers were genotyped. Analysis of the data was hampered by the size and complexity of the pedigree, which prohibited using exact multipoint methods on the entire kindred. Two-point parametric linkage analysis, using a conservative model of transmission, produced a maximum LOD score of 2.78 on chromosome 6, and a total of 39 loci with LOD scores >1.0. Multipoint parametric and non-parametric linkage analysis was performed separately on four sections of CR201, and interesting (nominal P-value from either analysis <0.01), although not statistically significant, regions were highlighted on chromosomes 1, 2, 3, 12, 16, 19, and 22, in at least one section of the pedigree, or when considering all sections together. The difficulties of analyzing genome wide SNP data for complex disorders in large, potentially informative, kindreds are discussed.
Assuntos
Transtorno Bipolar/genética , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Transtorno Bipolar/diagnóstico , Costa Rica , Feminino , Ligação Genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Genótipo , Humanos , Escore Lod , Masculino , LinhagemRESUMO
The current development of densely spaced collections of single nucleotide polymorphisms (SNPs) will lead to genomewide association studies for a wide range of diseases in many different populations. Determinations of the appropriate number of SNPs to genotype involve a balancing of power and cost. Several variables are important in these determinations. We show that there are different combinations of sample size and marker density that can be expected to achieve the same power. Within certain bounds, investigators can choose between designs with more subjects and fewer markers or those with more markers and fewer subjects. Which designs are more cost-effective depends on the cost of phenotyping versus the cost of genotyping. We show that, under the assumption of a set cost for genotyping, one can calculate a "threshold cost" for phenotyping; when phenotyping costs per subject are less than this threshold, designs with more subjects will be more cost-effective than designs with more markers. This framework for determining a cost-effective study will aid in the planning of studies, especially if there are choices to be made with respect to phenotyping methods or study populations.
Assuntos
Mapeamento Cromossômico/economia , Marcadores Genéticos/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Análise Custo-Benefício/economia , Frequência do Gene/genética , Genótipo , Humanos , Fenótipo , Projetos de Pesquisa , Tamanho da Amostra , Sensibilidade e EspecificidadeRESUMO
To study genetic loci influencing obesity in nuclear families with type 2 diabetes, we performed a genome-wide screen with 325 microsatellite markers that had an average spacing of 11 cM and a mean heterozygosity of approximately 75% covering all 22 autosomes. Genotype data were obtained from 562 individuals from 178 families from the Breda Study Cohort. These families were determined to have at least two members with type 2 diabetes. As a measure of obesity, the BMI of each diabetes patient was determined. The genotypes were analyzed using variance components (VCs) analysis implemented in GENEHUNTER 2 to determine quantitative trait loci influencing BMI. The VC analysis revealed two genomic regions showing VC logarithm of odds (LOD) scores > or =1.0 on chromosome 1 and chromosome 11. The regions of interest on both chromosomes were further investigated by fine-mapping with additional markers, resulting in a VC LOD score of 1.5 on chromosome 1q and a VC LOD of 2.4 on chromosome 11q. The locus on chromosome 1 has been implicated previously in diabetes. The locus on chromosome 11 has been implicated previously in diabetes and obesity. Our study to determine linkage for BMI confirms the presence of quantitative trait loci influencing obesity in subjects with type 2 diabetes on chromosomes 1q31-q42 and 11q14-q24.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Obesidade , Idoso , Análise de Variância , Índice de Massa Corporal , Feminino , Genótipo , Heterozigoto , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Locos de Características QuantitativasRESUMO
PURPOSE: Three forms of idiopathic partial epilepsy with autosomal dominant inheritance have been described: (a) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); (b) autosomal dominant lateral temporal epilepsy (ADLTE) or partial epilepsy with auditory features (ADPEAF); and (c) familial partial epilepsy with variable foci (FPEVF). Here we describe linkage analysis in a Dutch four-generation family with epilepsy fulfilling criteria of both ADNFLE and FPEVF. METHODS: Clinical characteristics and results of EEG, computed tomography (CT), and magnetic resonance imaging (MRI) were evaluated in a family with autosomal dominantly inherited partial epilepsy with apparent incomplete penetrance. Linkage analysis was performed with markers of the ADNFLE (1p21, 15q24, 20q13.3) and FPEVF (2q, 22q11-q12) loci. RESULTS: Epilepsy was diagnosed in 10 relatives. Age at onset ranged from 3 months to 24 years. Seizures were mostly tonic, tonic-clonic, or hyperkinetic, with a wide variety in symptoms and severity. Most interictal EEGs showed no abnormalities, but some showed frontal, central, and/or temporal spikes and spike-wave complexes. From two patients, an ictal EEG was available, showing frontotemporal abnormalities in one and frontal and central abnormalities in the other. Linkage analysis with the known loci for ADNFLE and FPEVF revealed linkage to chromosome 22q in this family. CONCLUSIONS: The clinical characteristics of this family fulfilled criteria of both ADNFLE and FPEVF. The frequent occurrence of seizures during daytime and the observation of interictal EEG abnormalities originating from different cortical areas were more in agreement with FPEVF. The observed linkage to chromosome 22q supported the diagnosis of FPEVF and confirmed that this locus is responsible for this syndrome.
Assuntos
Cromossomos Humanos Par 22/genética , Epilepsias Parciais/genética , Ligação Genética/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Eletroencefalografia/métodos , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , LinhagemRESUMO
Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated with contractions of the polymorphic D4Z4 repeat on chromosome 4qter. Almost half of new FSHD mutations occur postfertilization, resulting in somatic mosaicism for D4Z4. Detailed D4Z4 analysis of 11 mosaic individuals with FSHD revealed a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in 8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in 3 cases, the D4Z4 rearrangement resulted in two different-sized D4Z4 repeats, indicative of a gene conversion with crossover. In all cases, DNA markers proximal and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were intrachromosomal. We propose that D4Z4 rearrangements occur via a synthesis-dependent strand annealing model that relatively frequently allows for crossovers. Furthermore, the distribution of different cell populations in mosaic patients with FSHD suggests that mosaicism here results from D4Z4 rearrangements occurring during the first few zygotic cell divisions after fertilization.
Assuntos
Genes Homeobox , Mitose , Mosaicismo/genética , Distrofia Muscular Facioescapuloumeral/genética , Sequências Repetitivas de Ácido Nucleico , Telômero/genética , Alelos , Criança , Cromossomos Humanos Par 4/genética , Feminino , Conversão Gênica , Rearranjo Gênico , Humanos , Masculino , Linhagem , Fenótipo , Fatores de TempoRESUMO
We report further evidence for our previous suggestion [Garner et al., 2001: Am J Hum Genet 68:1061-1064] of a locus on 5q predisposing to bipolar I disorder (BP-I) in an extended Costa Rican pedigree. We genotyped additional microsatellite markers in this region and applied a multi-point non-parametric linkage analysis (SimWalk2). Significant identity-by-descent allele sharing among affected relatives was observed for all of the 20 markers tested in a segment of approximately 15 cM. Most affected individuals shared a single haplotype over this region; breaks within this haplotype may suggest a more restricted candidate location for a BP-I gene. These results support the suggestion that a locus at 5q31-33, together with a previously reported locus at 18q22-23, may provide the major genetic risk for BP-I in this family.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 5/genética , Haplótipos/genética , Linhagem , Mapeamento Cromossômico , Costa Rica , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVES: Celiac disease is caused by the interaction of multiple genes and environmental factors. Inheritance of the disease shows a complex pattern with a 10% sibling recurrence risk. The HLA-region is a major genetic risk locus in celiac disease, but genes outside this region are expected to contribute to the disease risk as well. The aim of this study was to identify the loci causing celiac disease in one large Dutch family with apparent dominant transmission of the disease. METHODS: The family comprised 17 patients in four generations, with possible transmission of the disease by both grandparents. Microsatellite markers evenly spread over all chromosomes were genotyped and linkage analysis was performed using both dominant and recessive disease models and a model-free analysis. RESULTS: Disease susceptibility in the family was linked to the HLA-region (lod score of 2.33) and all patients were HLA-DQ2. A dominantly inherited non-HLA locus with a maximum lod score of 2.61 was detected at 9p21-13, which was shared by 16 patients. Model-free analysis identified another possible non-HLA locus, at 6q25.3, which was shared by 14 patients (p = 0.01). Neither of these regions was detected in a genomewide screen in Dutch affected sibpairs, but the 9p21 locus has been implicated in Scandinavian families. CONCLUSIONS: Two potential non-HLA loci for celiac disease were identified in this large Dutch family. Our results provide replication of the Scandinavian 9p21 locus, and suggest that this locus plays a role in celiac disease patients from different Caucasian populations.
Assuntos
Doença Celíaca/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 9/genética , Ligação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , LinhagemRESUMO
OBJECTIVE: The relationship between smoking and colorectal cancer risk and whether such effect is modified by variations in the NAT2 genotype is investigated. METHODS: In the prospective DOM (Diagnostisch Onderzoek Mammacarcinoom; 27,722 women) cohort follow-up from 1976 until 1987 revealed 54 deaths due to colon or rectal cancer, and follow-up from 1987 to 01-01-1996 revealed 204 incident colorectal cancer cases. A random sample (n = 857) from the baseline cohort was used as controls. Four NAT2 restriction fragment length polymorphisms (RFLPs) were analysed using DNA extracted from urine samples. Rapid or slow acetylator phenotype status was attributed to individuals. RESULTS: Smoking may increase the risk for colon cancer (RR = 1.36, 95% CI 0.97-1.92) as well as for rectal cancer (RR = 1.31, 95% CI 0.76-2.25), although not statistically significant. Rapid NAT2 acetylation did not increase colorectal cancer risk, but in combination with smoking the risk was statistically significant increased, compared to women who had a slow NAT2 imputed phenotype and never smoked (RR = 1.56, 95% CI 1.03-2.37). For colon cancer, but not for rectal cancer the increased risk was statistically significant (RR = 1.67, 95% CI, 1.05-2.67 versus RR = 1.30 95% CI 0.63-2.68). CONCLUSIONS: Our study points to smoking as a risk factor for colon and rectal cancer and, in addition, especially in women with rapid NAT2 imputed phenotype.