RESUMO
In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3'-splice donor site in exon 4 and R385R was associated with a new 5'-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay.
Assuntos
Éxons/genética , Hipercolesterolemia/genética , Mutação , Splicing de RNA , Receptores de LDL/genética , Adolescente , Adulto , Idoso , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação/genética , Pseudoxantoma Elástico/genética , Transportadores de Cassetes de Ligação de ATP/química , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 16/genética , Análise Mutacional de DNA , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Genes Dominantes/genética , Genes Recessivos/genética , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Linhagem , Pseudoxantoma Elástico/patologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Deleção de Sequência/genéticaRESUMO
X linked congenital stationary night blindness (CSNBX) is a non-progressive retinal disorder characterised by decreased visual acuity and disturbance of night vision. CSNBX appears to be not only clinically but also genetically heterogeneous. On studying a single large family, we recently suggested the presence of a distinct locus for CSNBX in Xp21.1. Here, we describe the results of a linkage analysis in another large CSNBX family, which confirms this finding. Thus, the data presented here provide conclusive evidence for a distinct CSNBX locus in Xp21.1, closely linked to the X linked retinitis pigmentosa type 3 gene. The results combined with other published results indicate the order Xpter-DXS451-DMD-DYS1-(DXS1110, CSNBX1, XLRP3)-DXS7-(CSNBX2, XLRP2)-DXS14-Xcen.
Assuntos
Cegueira Noturna/genética , Cromossomo X , DNA/análise , Feminino , Ligação Genética , Humanos , Masculino , Cegueira Noturna/congênito , LinhagemRESUMO
Linkage analysis and homogeneity tests were carried out in 15 Dutch families segregating X-linked retinitis pigmentosa (X L R P). The study included segregation data for eight polymorphic DNA markers from the short arm of the human X chromosome. The results of both multipoint linkage analysis in individual families and heterogeneity analysis support the view that there are only two X L R P loci on the short arm of the human X chromosome, with one locus near the OTC gene and one in the vicinity of DXS255. Furthermore, our data confirm the hypothesis that a tapetal reflex in female carriers can be observed more frequently, if not exclusively, in X L R P families of the R P 3 type.
Assuntos
Ligação Genética/genética , Retinose Pigmentar/genética , Cromossomo X , Adolescente , Mapeamento Cromossômico , DNA/análise , Sondas de DNA , Feminino , Heterogeneidade Genética , Marcadores Genéticos , Humanos , Masculino , Países Baixos , Linhagem , Reação em Cadeia da PolimeraseRESUMO
X-linked congenital stationary night blindness (CSNBX) is a non-progressive retinal disorder characterized by decreased visual acuity and loss of night vision. CSNBX is clinically heterogeneous with respect to the involvement of retinal rods and/or cones in the disease. In this study, we localize a new locus for CSNBX to Xp21.1, thus providing evidence that CSNBX is also genetically heterogeneous. A clear correlation between different genotypes and phenotypes cannot be found yet. The new CSNBX gene described here is closely linked to the X-linked retinitis pigmentosa type 3 gene region, which supports the hypothesis that there may be a functional relationship between congenital stationary night blindness and retinitis pigmentosa.
Assuntos
Ligação Genética , Cegueira Noturna/genética , Retinose Pigmentar/genética , Cromossomo X , Mapeamento Cromossômico , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Retinose Pigmentar/classificaçãoRESUMO
X-linked progressive cone dystrophy (XLPCD) is characterized by progressive macular atrophy, abnormal colour vision, reduced cone responses in ERG, and reduced visual acuity. XLPCD may be genetically heterogeneous. Therefore, carrier detections by DNA analysis may only be carried out in those families in which the position of the gene locus can be clearly established. Here, we describe the first DNA carrier detections in XLPCD.
Assuntos
DNA/análise , Triagem de Portadores Genéticos , Ligação Genética , Retinose Pigmentar/genética , Cromossomo X , Feminino , Humanos , Escore Lod , Masculino , LinhagemRESUMO
Linkage analysis was carried out in a Dutch family with Nance-Horan (NH) syndrome. Close linkage without recombination between NH and the Xp loci DXS207, DXS43, and DXS365 (zmax = 3.23) was observed. Multipoint linkage analysis and the analysis of recombinations in multiple informative meioses suggest the genetic order Xcen-DMD (exon 49)-DXS451-(NH, DXS207, DXS365, DXS43)-(STS, DXF30)-Xpter. These data refine the localization of the NH locus on the distal Xp.
Assuntos
Anormalidades Múltiplas/genética , Catarata/genética , Orelha/anormalidades , Microftalmia/genética , Anormalidades Dentárias/genética , Cromossomo X , Feminino , Genes Recessivos , Haplótipos/genética , Humanos , Escore Lod , Masculino , Meiose , Países Baixos , Linhagem , SíndromeAssuntos
Retinose Pigmentar/genética , Cromossomo X , Mapeamento Cromossômico , Feminino , Humanos , Masculino , LinhagemRESUMO
Although physical and genetic mapping studies assigned the X-linked ocular albinism gene to Xp22.3, the exact gene order in this region is still unclear. We present additional genetic mapping data concerning X-linked ocular albinism that suggests the consensus order Xpter-STS-DXS237-KAL-(OA1, DXS143)-DXS85-DXS16-Xcen.
Assuntos
Albinismo Ocular/genética , Ligação Genética , Cromossomo X , Mapeamento Cromossômico , Feminino , Humanos , Síndrome de Kallmann/genética , Masculino , LinhagemRESUMO
Differential Alu PCR fingerprint cloning was used to isolate a DNA probe from the Xp11.4-->p11.21 region of the human X chromosome. This novel sequence, cpXr318 (DXS742), detects a new submicroscopic deletion interval at the Norrie disease locus (NDP). Combining our data with the consensus genetic map of the proximal short arm of the X chromosome, we propose the physical order Xcen-DXS14-DXS255-(DXS426, TIMP)-(DXS742-([MAOB-MAOA-DXS7], NDP)-DXS77-DXS228)-DXS209-DXS148-DXS196-++ +Xpter. The cpXr318 probe and a subclone from a cosmid corresponding to the DXS7 locus were converted into sequence-tagged sites. Finally, DXS742, DSX7, DXS77, and MAOA were integrated into a physical map spanning the Norrie disease locus.
Assuntos
Cegueira/genética , Deleção Cromossômica , Sondas de DNA , Cromossomo X , Sequência de Bases , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Marcadores Genéticos , Humanos , Células Híbridas , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido Nucleico , Mapeamento por Restrição , Retina/anormalidades , Sitios de Sequências RotuladasRESUMO
X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and several closely linked RFLP loci have been identified. Linkage analysis and deletion mapping have established the marker gene order Xpter-STS-DX237-(OA1,DXS143,DXS85)-DXS1 6-DXS43-Xcen. Although the position of OA1 has yet not been fully resolved, we report on the first carrier detections in OXA of the Nettleship-Falls type by DNA analysis using markers which unquestionably flank OA1.
Assuntos
Albinismo Ocular/genética , Triagem de Portadores Genéticos , Cromossomo X , DNA , Feminino , Ligação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
An extensive linkage analysis was performed by studying ten Xp22 loci in ten families segregating for X-linked ocular albinism of the Nettleship-Falls type (XOA). Linkage was confirmed between the XOA locus (OA1) and both DXS16 (theta max = 0.10, zeta max = 4.09) and DXS237 (theta max = 0.12, zeta max = 2.53). Linkage was found between OA1 and the loci DXS85 (theta max = 0.00, zeta max = zeta max = 4.37), DXS143 (theta max = 0.04, zeta max = 3.74), STS (theta max = 0.05, zeta max = 2.48), DXF30S1 (DXS278) (theta max = 0.07, zeta max = 8.79) and DXF30S2/3 (DXS278) (theta max = 0.00, zeta max = 14.93). An indication for linkage was found between OA1 and the loci DXS43 (theta max = 0.10, zeta max = 1.58) and DXS31 (theta max = 0.12, zeta max = 1.55). The analysis of multiple informative meioses suggests the order Xpter-(DXS31, DXS89)-(DXF30S1, DXS237)-(DXF30S2/3, OA1)-DXS143-(DXS16, DXS43)-Xcen. Various multipoint linkage analyses using the DNA loci order DXF30S1-STS-DXS237-DXS143-DXS16 significantly favour the position of OA1 between DXS237 and DXS143. These results further determine the genetic map around the XOA locus on the distal Xp and may be useful for DNA diagnosis in families with XOA.
