RESUMEN
Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.
Asunto(s)
Reordenamiento Génico , Incontinencia Pigmentaria/genética , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Exones , Femenino , Humanos , Quinasa I-kappa B , Incontinencia Pigmentaria/embriología , Masculino , Datos de Secuencia Molecular , Mutación , FN-kappa B/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We report a new locus, designated JC-1, which maps between the gene responsible for adrenal hypoplasia (AHC) and the gene that encodes glycerol kinase (GK) in Xp21.2-21.3. The probe identifying this locus was obtained by cloning the distal sequence of a junction fragment from a Duchenne muscular dystrophy (DMD) patient with a large deletion. Pulsed-field gel electrophoresis analysis shows that a region of at least 4 Mb separates the 3' end of the dystrophin gene and the closest distal marker to AHC, DXS28. This region of the human genome contains few genes whose deletion results in a clinical phenotype. JC-1 is a useful probe from which to initiate strategies directed at cloning the AHC and GK loci.
Asunto(s)
Distrofias Musculares/genética , Cromosoma X , Southern Blotting , Línea Celular , Mapeo Cromosómico , Clonación Molecular , ADN/aislamiento & purificación , Electroforesis en Gel de Agar , Glicerol Quinasa/genética , Humanos , Hibridación de Ácido Nucleico , Virilismo/genéticaRESUMEN
A panel of patients with Duchenne and Becker muscular dystrophy (DMD and BMD) has been screened with the cDNA probes Cf56a and Cf23a, which detect exons in the central part of the DMD gene. One or more exons were deleted in 60% of patients. The deletions were mapped and prove to be heterogeneous in size and extent, particularly in DMD. Deletions specific to DMD and to BMD are described. Half of all BMD patients have a deletion of one particular small group of exons; smaller deletions within this same group produce the more severe DMD.
Asunto(s)
Deleción Cromosómica , Exones , Distrofias Musculares/genética , Cromosoma X , Femenino , Humanos , Masculino , Mapeo RestrictivoRESUMEN
We have studied patients with Duchenne muscular dystrophy (DMD), DMD together with glycerol kinase (GK) deficiency, or DMD together with both GK deficiency and congenital adrenal hypoplasia (AHC). Analysis of deletions in these patients allows the mapping of these mutations in Xp21. The following order is proposed: Xpter - L1 - AHC - GK - DMD - Xcen. One of the boys with DMD, GK, and AHC is shown by pulsed-field-gel electrophoresis to have a deletion which has a proximal endpoint at least 500 kb distal from the pERT87 (DXS164) locus.
Asunto(s)
Insuficiencia Suprarrenal/congénito , Deleción Cromosómica , Glicerol Quinasa/deficiencia , Fosfotransferasas/deficiencia , Cromosoma X , Fosfatasa Ácida/metabolismo , Insuficiencia Suprarrenal/enzimología , Insuficiencia Suprarrenal/genética , Línea Celular , Niño , Preescolar , Mapeo Cromosómico , ADN/genética , Glicerol Quinasa/genética , Glicerol Quinasa/metabolismo , Humanos , Masculino , Aberraciones Cromosómicas SexualesRESUMEN
It is now possible to map almost any disease locus to a chromosomal region in the human genome by family studies with restriction fragment length polymorphisms. Duchenne and Becker muscular dystrophies have been shown to be localized within the same small region of Xp21 on the human X chromosome. Myotonic dystrophy has been localized to a region close to the centromere of chromosome 19. Technologies are now available to identify candidate genes for the diseases. Autosomal recessive muscular dystrophies are more difficult to study, but even these will be amenable to analysis in the very near future. The next decade should witness some exciting advances in the molecular analysis and clinical management of human muscular dystrophies.
Asunto(s)
Distrofias Musculares/genética , Mapeo Cromosómico , Cromosomas/análisis , ADN/análisis , Electroforesis/métodos , Código Genético , Ligamiento Genético , Marcadores Genéticos , Humanos , Distrofias Musculares/clasificación , Distrofias Musculares/fisiopatologíaRESUMEN
We have used chromosome jumping technology to move from within a large intron sequence in the Duchenne muscular dystrophy (DMD) gene to a region adjacent to exons of the gene. The single copy jump clone, HH1, was used to characterise deletions in patients previously shown to be deleted for DNA markers in the 5' end of the gene. 12 out of 15 such patients have breakpoints which lie between HH1 and the genomic locus J-47. Thus the vast majority of the deletions in these patients have proximal breakpoints in a similar region distal to the 5' end of the gene. HH1 was mapped with respect to the X;1 translocation in a DMD female and was shown to lie at least 80 kb from the starting point of the chromosome jump, HIP25.
Asunto(s)
Deleción Cromosómica , Mapeo Cromosómico , Distrofias Musculares/genética , Línea Celular , Clonación Molecular , ADN/genética , Exones , Humanos , Intrones , Masculino , Hibridación de Ácido Nucleico , Plásmidos , Valores de ReferenciaRESUMEN
We have isolated a DNA sequence (HIP25) by subtraction- hybridisation which is deleted in a number of Duchenne muscular dystrophy (DMD) patients. HIP25 is conserved in evolution and hybridises to human fetal and adult muscle mRNA. HIP25 is absent in human fetal fibroblast mRNA. Physical mapping data localise this sequence within Xp21 between the breakpoints of X;autosome translocations found in two females suffering from the disease. HIP25 is a candidate exon sequence for the basic defect in DMD boys deleted at this locus.