RESUMO
Restless legs syndrome (RLS) is a common, sleep-related movement disorder. The symptoms follow a circadian pattern, worsening in the evening or night, leading to sleep disruption and daytime somnolence. Familial forms of RLS have been described and usually display an autosomal dominant pattern of inheritance. To date, linkage analysis has identified nine RLS loci, but no specific causative gene has been reported. Association mapping has highlighted a further four genomic areas of interest. We have conducted a genome-wide linkage analysis in an Irish autosomal dominant RLS pedigree with 11 affected members. Significant linkage was found on chromosome 19p for a series of microsatellite markers, with a maximum two-point LOD score of 3.59 at θ = 0.0 for marker D19S878. Recombination events, identified by haplotype analysis, define a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to an interval of 2.5 Mb. This study provides evidence of a novel RLS locus and provides further evidence that RLS is a genetically heterogenous disorder.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 19/genética , Ligação Genética , Predisposição Genética para Doença/genética , Síndrome das Pernas Inquietas/genética , Adulto , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a genetic disorder of corneal endothelial cells resulting in corneal clouding and visual impairment. Autosomal dominant (CHED1) and autosomal recessive (CHED2) forms have been reported and map to distinct loci on chromosome 20. CHED2 is caused by mutations in the SLC4A11 gene which encodes a membrane transporter protein. MATERIALS AND METHODS: Members of a large CHED2 family were recruited for clinical and genetic studies. Genomic DNA was sequenced for the exons and intron-exon boundaries of the SLC4A11 gene. RESULTS: Twelve family members were recruited, of which eight were diagnosed with CHED. A homozygous SLC4A11 mutation (Leu843Pro) was detected in the eight patients; a single copy of the mutation was present in three unaffected carriers. CONCLUSIONS: A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state.
Assuntos
Proteínas de Transporte de Ânions/genética , Antiporters/genética , Distrofias Hereditárias da Córnea/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Consanguinidade , Distrofias Hereditárias da Córnea/diagnóstico , Análise Mutacional de DNA , Éxons/genética , Feminino , Homozigoto , Humanos , Íntrons/genética , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
Linkage of IBD to the pericentromeric region of chromosome 16 has been widely confirmed by analyses of multiple populations. The NOD2 gene is located in the peak region of linkage on chromosome 16 and thought to be involved in the activation of nuclear factor (NF) kappaB in response to bacterial components. Mutations in the NOD2 gene are found to be strongly associated with susceptibility to Crohn's disease (CD). A total of 65 Irish CD families were genotyped to determine if NOD2 mutations conferred susceptibility to CD and the prevalence of these mutations in sporadic and familial forms of the disease. The Irish population is relatively homogenous and thus may provide advantages in genetic studies of complex diseases. We confirmed the IBD1 locus as a susceptibility locus for IBD within the Irish population by linkage analysis followed by linkage disequilibrium studies. No significant evidence of linkage was observed to the previously identified regions on chromosomes 1, 12 and 14. In all, 131 CD affected families were then genotyped for seven of the previously published NOD2 single-nucleotide polymorphisms (SNPs). Allelic transmission distortion was investigated using the pedigree disequilibrium test (PDT). SNP13 (3020insC) was found to be associated with CD (P=0.0186). Patients who possessed a rare allele of SNP8, 12 or 13 presented earlier when compared to patients without rare variants (mean age, 20.1 vs 24 years, P=0.011) and the rare allele of SNP13 was observed to be predominantly linked to ileal disease (P=0.02). This report confirms the importance of NOD2 as a susceptibility gene for CD within the Irish population.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 16/genética , Doença de Crohn/genética , Peptídeos e Proteínas de Sinalização Intracelular , Mutação/genética , Adulto , Alelos , Análise Mutacional de DNA , Primers do DNA , Testes Genéticos , Humanos , Irlanda , Desequilíbrio de Ligação , Repetições de Microssatélites , Proteína Adaptadora de Sinalização NOD2 , LinhagemRESUMO
OBJECTIVE: We studied a large Irish Caucasian pedigree with familial hemiplegic migraine (FHM) with the aim of finding the causative gene mutation. BACKGROUND: FHM is a rare autosomal-dominant subtype of migraine with aura, which is linked to 4 loci on chromosomes 19p13, 1q23, 2q24, and 1q31. The mutations responsible for hemiplegic migraine have been described in the CACNA1A gene (chromosome 19p13), ATP1A2 gene (chromosome 1q23), and SCN1A gene (chromosome 2q24). METHODS: We performed linkage analyses in this family for chromosome 1q23 and performed mutation analysis of the ATP1A2 gene. RESULTS: Linkage to the FHM2 locus on chromosome 1 was demonstrated. Mutation screening of the ATP1A2 gene revealed a G to C substitution in exon 22 resulting in a novel protein variant, D999H, which co-segregates with FHM within this pedigree and is absent in 50 unaffected individuals. This residue is also highly conserved across species. CONCLUSIONS: We propose that D999H is a novel FHM ATP1A2 mutation.