RESUMEN
Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a DNA duplication at chromosome 17p11.2. In view of the point mutation in the gene for peripheral myelin protein pmp-22/gas-3 in Trembler mice, a murine model for CMT1A, we have analysed whether this gene is altered in CMT1A. Here we show that the human homologue of the murine pmp-22 gene is located within the CMT1A DNA duplication, which is a direct repeat and does not interrupt the coding region of PMP-22. Expression of PMP-22 in CMT1A fibroblasts is similar to expression in control fibroblasts. Increased gene dosage or altered PMP-22 expression in the peripheral nervous system are therefore possible mechanisms by which PMP-22 is involved in CMT1A.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Secuencia de Bases , Enfermedad de Charcot-Marie-Tooth/clasificación , ADN/genética , Expresión Génica , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Eliminación de Secuencia , Secuencia de Aminoácidos , Secuencia de Bases , Enfermedad de Charcot-Marie-Tooth/clasificación , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Codón , Femenino , Genes , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Proteína P0 de la Mielina , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
Bethlem myopathy is a rare autosomal dominant myopathy characterized by slowly progressive limb-girdle muscular atrophy and weakness, and contractures of multiple joints. To identify the genetic localization we used highly polymorphic microsatellite markers in a genome-wide search in six Dutch families. After excluding genetic linkage with 52 markers distributed evenly over the autosomes, significant linkage was present with the 21q22.3 locus PFKL (two-point lod score of Zmax = 6.86 at theta = 0.03). There was no indication of genetic heterogeneity. The pattern of recombinations observed with adjacent markers indicated a localization distal to PFKL. Recombination of a marker within the collagen 6a1 gene (COL6A1) excluded this apparent candidate gene in one of the Bethlem myopathy families. The disease gene is most likely located in the region between COL6A1 and the telomere of chromosome 21q.
Asunto(s)
Mapeo Cromosómico , Extremidades , Atrofia Muscular/genética , Niño , Preescolar , Colágeno/genética , Femenino , Genes Dominantes , Ligamiento Genético , Humanos , Recién Nacido , Masculino , Repeticiones de MicrosatéliteRESUMEN
The most frequently found mutation in autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) is a large duplication on chromosome 17p11.2 containing probes VAW409R3, VAW412R3, and EW401. We investigated a family with severe features of HMSN I, and demonstrated the absence of this duplication by a quantitative analysis of the hybridization signals of VAW409R3 and VAW412R3. Linkage analysis, however, revealed linkage with probe VAW409R3a (lod score, 3.22), which demonstrates the existence of allelic heterogeneity within the HMSN Ia locus. These findings have implications for clinical practice and for investigating the identity of the HMSN Ia gene.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Cromosomas Humanos Par 17 , Mutación , Adulto , Alelos , Southern Blotting , Mapeo Cromosómico , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Femenino , Marcadores Genéticos , Humanos , Masculino , Familia de Multigenes , Linaje , Mapeo RestrictivoRESUMEN
X-linked recessive myotubular myopathy (XLMTM) is a rare and severe neonatal neuromuscular disease characterized by muscle weakness, hypotonia, and respiratory problems. Here we report an extensive linkage analysis in two families with XLMTM. Using 18 markers in the Xq27-Xqter region we found a maximum two-point lod score of Z = 4.00 at theta = 0.00 for the marker II-10 (DXS466). Three recombinations were detected between markers and the disease locus. At the distal side of Xq27.3 a recombination was present in between RNI (DXS369) and VK23b (DXS297), another in between VK23b (DXS297) and II-10 (DXS466), and at the proximal side of Xq28 a recombination in between U6.2 (DXS304) and Cpx67 (DXS134). Combining the results of both families we conclude that XLMTM is located in the 8 Mb(11 cM) region between VK23b (DXS297) and Cpx67 (DXS134).
Asunto(s)
Ligamiento Genético , Microtúbulos/metabolismo , Enfermedades Neuromusculares/genética , Cromosoma X , Adulto , Mapeo Cromosómico , Sondas de ADN , Marcadores Genéticos , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/ultraestructura , Enfermedades Neuromusculares/metabolismo , Hibridación de Ácido Nucleico , LinajeRESUMEN
X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria is clinically characterized by congenital dilated cardiomyopathy, skeletal myopathy, recurrent bacterial infections, and growth retardation. We analyzed linkage between the disease locus and X-chromosomal markers in a family with seven carriers, four patients, and eight unaffected sons of carriers. Highest lod scores obtained by two-point linkage analysis were 2.70 for St14.1 (DXS52, TaqI) at a recombination fraction of zero and 2.53 for cpX67 (DXS134) at a recombination fraction of zero. Multipoint linkage analysis resulted in a maximum lod score of 5.24 at the position of St35.691 (DXS305). The most distal recombination detected in this family was located between the markers II-10 (DXS466) and DX13 (DXS15). These data indicate the location of the mutated gene at Xq28.
Asunto(s)
Cardiomiopatías/genética , Mapeo Cromosómico , Ligamiento Genético , Mitocondrias/patología , Neutropenia/genética , Cromosoma X/ultraestructura , Cardiomiopatías/complicaciones , Femenino , Tamización de Portadores Genéticos , Marcadores Genéticos , Humanos , Masculino , Neutropenia/complicaciones , Linaje , Recombinación Genética , SíndromeRESUMEN
Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/diagnóstico , ADN/análisis , Autorradiografía , Southern Blotting , Enfermedad de Charcot-Marie-Tooth/genética , Sondas de ADN , Humanos , Hibridación de Ácido NucleicoRESUMEN
The clinical features and disease course of six patients from a family with autosomal dominant inheritance of presenile dementia and a hypokinetic syndrome are described. In the past, these patients have carried diagnoses of Pick's disease, Huntington's disease, Parkinson-dementia, and one patient was described as suffering from a 'peculiar type of presenile dementia' in a case report. In the two cases examined, the most distinctive neuropathological features were extensive globular deposits of periodic acid-Schiff plus diastase (PAS)-positive material, having tinctural properties of amyloid only to a limited degree, in the cerebellum and cerebral cortex. These globules stained positively with antibodies against prion protein. Southern blot of MspI-digested genomic DNA showed an abnormal band of approximately 950 bp in all three patients from which material was available. Direct sequencing of the abnormal allele revealed an insert consisting of eight extra 24-nucleotide repeats in the patients, which was absent in a healthy first degree relative who was considered well beyond the age of onset of symptoms in this family. The nucleotide sequence of the abnormal insert of 192 bp was different from that of a previously described insert of equal length. Adding to previous descriptions of mutations in the prion protein gene, this report emphasizes the clinical, neuropathological and genetic heterogeneity of inherited prion disease.
Asunto(s)
Elementos Transponibles de ADN , Demencia/genética , Hipocinesia/genética , Enfermedades por Prión/genética , Enfermedades por Prión/metabolismo , Priones/genética , Adulto , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Demencia/metabolismo , Demencia/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biología Molecular , Datos de Secuencia Molecular , Linaje , Enfermedades por Prión/patología , Priones/metabolismoRESUMEN
Single-strand conformational polymorphisms (SSCP) of the connexin32 gene were analyzed in 121 patients possibly affected by Charcot-Marie-Tooth (CMT) disease. The 121 patients were selected from 443 possible CMT/HNPP (hereditary neuropathy with liability to pressure palsies) patients based on genetic linkage to Xq13.1, absence of the 17p12 duplication and deletion, and absence of point mutations in PMP22 and P0. We found five new mutations at nucleotides 105 (C-T), 316 (C-G), 321 (C-T), 328 (T-C), and 657 (G-C), and three mutations at nucleotide 126 (C-T), 249 (G-A), and 477 (G-A) previously described in other unrelated families. The nucleotide changes resulted in seven amino-acid substitutions and one premature stop codon.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Mutación Puntual , Cromosoma X , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Femenino , Genes Dominantes , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/genética , Proteína beta1 de Unión ComunicanteRESUMEN
Recently, it has been shown that Charcot-Marie-Tooth disease type 1a (CMT1a) is linked with a duplication of a DNA segment that is detected by probe VAW409R3, and that is located on chromosome 17p11.2. Here, we show that this duplication also contains VAW412R3a, but not A10-41 and EW503. Accounting for the duplication in recombination analysis, we found recombinants between CMT1a and EW301 and EW502, but not with A10-41, VAW409R3, and VAW412R3. Using pulsed-field gel electrophoresis analysis, we estimated the minimal size of the duplicated region in CMT1a patients to be 1100 kb.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 17 , Ligamiento Genético/genética , Familia de Multigenes/genética , Southern Blotting , Desoxirribonucleasa HpaII , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Electroforesis en Gel de Campo Pulsado , Femenino , Marcadores Genéticos/genética , Humanos , MasculinoRESUMEN
Isolated cases of hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) have been thought to be most frequently autosomal recessive. We have found that a recently discovered duplication in chromosome 17, responsible for most cases of autosomal dominant HMSN I, is present as a de-novo mutation in 9 out of 10 sporadic patients. This finding has important implications for genetic counselling of isolated patients with HMSN I.