Asunto(s)

Células Sanguíneas/ultraestructura , Neoplasias Colorrectales/genética , Inactivación del Cromosoma X , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad

RESUMEN

The aetiology of multiple sclerosis (MS) is unknown. Autoimmune mechanisms are most probably involved. Loss of immunological tolerance to self-antigens is a common feature of autoimmune disorders. Response to X-linked self-antigens could be influenced by X-chromosome inactivation, and contribute to the gender bias observed in autoimmune disorders. Previous studies have indicated an association between skewed X inactivation and autoimmune thyroid disease and scleroderma. To investigate a potential role of X inactivation in MS, we compared the X-inactivation pattern in 568 female MS patients with controls. We found no difference in degree of skewing between patients (median 64%) and controls (median 65%) (P = 0.474). The X-inactivation pattern did thus not explain the female predominance of MS patients in general. As the aetiology of different subgroups of MS may differ, patients were grouped according to disease course: relapsing-remitting (RR-MS), secondary progressive (SP-MS) and primary progressive (PP-MS). A comparison of the X-inactivation pattern between subgroups indicated a possible difference in degree of skewing between patients with a progressive versus a relapsing course (P = 0.05).

Asunto(s)

Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Inactivación del Cromosoma X/genética , Adulto , Factores de Edad , Anciano , Interpretación Estadística de Datos , Femenino , Variación Genética/genética , Humanos , Persona de Mediana Edad , Modelos Genéticos , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Factores Sexuales

RESUMEN

The X chromosome inactivation pattern in peripheral blood cells becomes more skewed after age 55, and a genetic effect on this age-related skewing has been reported. We investigated the effect of age on X inactivation phenotype in blood, buccal cells and tissue from duodenal biopsies in 80 females aged 19-90 years. The X inactivation pattern correlated positively with age in blood (r = 0.238, P = 0.034) and buccal cells (r = 0.260, P = 0.02). The mean degree of skewing was higher in the elderly (>/=55 years) than in the young (<55 years) in blood (70.1 and 63.5%, respectively, P = 0.013) and in buccal cells (64.7 and 59.0%, respectively, P = 0.004). Correlation of X inactivation between the different tissues was high in all tissues with a tendency to increase with age for blood and buccal cells (P = 0.082). None of the duodenal biopsies had a skewed X inactivation, and the mean degree of skewing was similar in the two age groups. The tendency for the same X chromosome to be the preferentially active X in both blood and buccal cells with advancing age is in agreement with a genetic effect on age-related skewing and indicates that genes other than those involved in hematopoiesis should be investigated in the search for genes contributing to age related skewing.

Asunto(s)

Envejecimiento , Células Sanguíneas/citología , Cromosomas Humanos X , Inactivación del Cromosoma X , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Mejilla , ADN/metabolismo , Duodeno/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Fenotipo

RESUMEN

The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.

Asunto(s)

Huesos/anomalías , Diafragma/fisiopatología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Mutación/genética , Proteínas Tirosina Fosfatasas/genética , Adulto , Preescolar , Análisis Mutacional de ADN , Diafragma/patología , Femenino , Lateralidad Funcional/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Heterocigoto , Humanos , Recién Nacido , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Debilidad Muscular/patología , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/fisiopatología , Linaje , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras , Inactivación del Cromosoma X/genética

RESUMEN

BACKGROUND: A higher frequency of skewed X chromosome inactivation has been reported in a consecutive series of young patients with breast cancer compared with controls of a similar age. OBJECTIVE: To investigate the X inactivation pattern in patients with familial non-BRCA1/BRCA2 breast cancer (n = 272), BRCA1/BRCA2 germline mutations (n = 35), and sporadic breast cancer (n = 292). METHODS: X inactivation pattern was determined by polymerase chain reaction analysis of the highly polymorphic CAG repeat in the androgen receptor (AR) gene. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially expressed one X chromosome. RESULTS: Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation (11.2%) than young controls (2.7%) (p = 0.001). There was also a strong tendency for middle aged patients with sporadic breast cancer to be more skewed than middle aged controls (13.6% v 4.4%) (p = 0.02). No association between skewed X inactivation and breast cancer was found for the BRCA1/BRCA2 patients . CONCLUSIONS: Skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X linked genes.

Asunto(s)

Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Cromosomas Humanos X , Polimorfismo Genético , Inactivación del Cromosoma X , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Salud de la Familia , Femenino , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Inactivación del Cromosoma X/genética

RESUMEN

X-linked myotubular myopathy is a rare severe muscle disorder in affected male neonates. Most female carriers are free from symptoms. Skewed X inactivation has been proposed to be responsible for the affected phenotype seen in some carriers. We have compared the X inactivation patterns in blood DNA with the clinical phenotype in carriers of X-linked myotubular myopathy. The X-inactivation analysis was performed using HpaII predigestion of DNA followed by polymerase chain reaction of the highly polymorphic CAG repeat of the androgen receptor (AR) gene. The frequency of skewed X inactivation was similar in the X-linked myotubular myopathy carriers (22%) and in 235 controls (18%). Three overtly affected carriers had skewed X inactivation with the mutated X as the predominantly active X in at least two of them. Four females with mild symptoms had random X inactivation. The unaffected X-linked myotubular myopathy carriers had either skewed X inactivation in favour of expression from the normal X or random X-inactivation. Thus, there was a tendency for females with a more severe phenotype to have a skewed pattern of X inactivation, while females with an intermediate phenotype had a random pattern of X-inactivation.

Asunto(s)

Compensación de Dosificación (Genética) , Heterocigoto , Miopatías Estructurales Congénitas/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Fenotipo , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos

Asunto(s)

Síndrome de Angelman/genética , Impresión Genómica/genética , Inyecciones de Esperma Intracitoplasmáticas/efectos adversos , Adulto , Autoantígenos , Preescolar , Cromosomas Humanos Par 15/genética , Metilación de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Ribonucleoproteínas Nucleares Pequeñas/genética , Proteínas Nucleares snRNP

RESUMEN

X-linked myotubular myopathy is a severe congenital myopathy in males, caused by mutations in the myotubularin (MTM1) gene on chromosome Xq28. In heterozygous carriers of MTM1 mutations, clinical symptoms are usually absent or only mild. We report a 6-year-old girl presenting at birth with marked hypotonia and associated feeding and respiratory difficulties. A muscle biopsy performed at 5 months suggested a diagnosis of myotubular myopathy. On examination at 6 years she had marked facial weakness with bilateral ptosis and external ophthalmoplegia, severe axial and proximal weakness and a mild scoliosis. Muscle magnetic resonance imaging showed a distinctive pattern of muscle involvement. Molecular genetic investigation of the MTM1 gene identified a heterozygous mutation in exon 12. X-inactivation studies in lymphocytes showed an extremely skewed pattern (97:3). This case emphasizes that investigation of the MTM1 gene and X-inactivation studies are indicated in isolated females with histopathological and clinical findings suggestive of myotubular myopathy.

Asunto(s)

Cromosomas Humanos X , Compensación de Dosificación (Genética) , Ligamiento Genético , Miopatías Estructurales Congénitas/genética , Proteínas Tirosina Fosfatasas/genética , Niño , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Hipotonía Muscular , Miopatías Estructurales Congénitas/patología , Oftalmoplejía , Aberraciones Cromosómicas Sexuales

RESUMEN

INTRODUCTION: Patients with invasive ovarian cancer were recently shown to have a higher frequency of skewed X chromosome inactivation in peripheral blood cells compared to patients with borderline cancer and controls. In this study, we analysed the X inactivation pattern in peripheral blood from 216 breast cancer patients. METHODS: X inactivation analysis was performed using HpaII predigestion of DNA followed by PCR of the highly polymorphic CAG repeat of the androgen receptor gene (AR), which amplifies the undigested inactive X chromosome only. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially used one X chromosome. RESULTS: Young breast cancer patients (27-45 years) had a higher frequency of skewed X inactivation than young controls (13 and 1%, respectively) (p=0.009), whereas no difference was found for middle aged and older patients compared to controls of a similar age. CONCLUSIONS: A germline mutation in an X linked tumour suppressor gene may give a proliferative advantage to cells with this mutation on the active X chromosome, thus causing skewed X inactivation and an increased risk for developing cancer. Another possible explanation could be that females with a constitutionally skewed X inactivation pattern are more susceptible to develop breast cancer because of an X linked low penetrance susceptibility allele that is affected by the inactivation pattern.

Asunto(s)

Neoplasias de la Mama/genética , Compensación de Dosificación (Genética) , Cromosoma X/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Repeticiones de Trinucleótidos/genética

RESUMEN

BACKGROUND: Monogenic inherited disorders are caused by a mutation in one single gene. Each of these disorders is very rare, but as there are many thousand different monogenic disorders, they represent a significant health problem. Most monogenic disorders are severe and have no cure. Gene therapy will therefore often be the only possible treatment. MATERIAL AND METHODS: Characterisation of the gene is necessary for the development of gene therapy, and at the present time only a limited number of the genes in relation to the total number of the severe monogenic disorders is known. RESULTS: Clinical trials for some of the monogenic disorders, such as cystic fibrosis, have been going on for many years. INTERPRETATION: In spite of the tremendous effort, it is so far not documented that patients have been cured of a monogenic disorder by gene therapy.

Asunto(s)

Fibrosis Quística/terapia , Terapia Genética , Errores Innatos del Metabolismo/terapia , Protocolos Clínicos , Ensayos Clínicos como Asunto , Fibrosis Quística/genética , Humanos , Errores Innatos del Metabolismo/genética

RESUMEN

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Asunto(s)

Cromosomas Humanos Par 8/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Mutación/genética , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Antropometría , Secuencia de Bases , Estatura , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Factores de Unión al ADN Específico de las Células Eritroides , Exones/genética , Femenino , Genotipo , Humanos , Lactante , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/fisiopatología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Radiografía , Síndrome , Factores de Transcripción/metabolismo , Dedos de Zinc/genética

RESUMEN

Despite differences in research traditions, the disciplines of genetics, epidemiology, and demography are becoming increasingly integrated in health-related research. The enormous development within genetic technology, with the possibility of genotyping thousands of variants from small samples of biological material obtained by non-invasive methods, now makes it feasible to include genetic information in epidemiologic and demographic studies. Simultaneously, new insight can be obtained from hybrids of methods and data from the three disciplines. This paper illustrates how a genetic observation combined with demographic insight and a modified genetic-epidemiologic design (a twin study) provides evidence that part of the sex difference in survival can be attributed to the fact that females have two X chromosomes and males have only one, a result that is of potential interest for genetics, epidemiology, and demography.

Asunto(s)

Demografía , Epidemiología , Genética , Mortalidad , Gemelos Monocigóticos/genética , Cromosoma X/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia

RESUMEN

Major characteristics of the acrocallosal syndrome include severe mental retardation, agenesis or hypoplasia of the corpus callosum, and polydactyly of fingers and toes. In the past few years, anencephaly has also been noted, together with other midline defects. We report on a nonconsanguineous, Norwegian couple with a history of two pregnancies with a male and a female fetus, respectively, with anencephaly, median cleft lip and palate, omphalocele, and preaxial polydactyly, suggesting the diagnosis of the acrocallosal syndrome. Both fetuses also lacked eyes and nose, a finding not previously reported in the acrocallosal syndrome. Microphthalmia has been reported in the hydrolethalus syndrome, which may be caused by mutations in the same gene as the acrocallosal syndrome. The present report adds support to the hypothesis that the acrocallosal and hydrolethalus syndromes may be allelic conditions. The family history is consistent with autosomal recessive inheritance.

Asunto(s)

Anomalías Múltiples/diagnóstico por imagen , Agenesia del Cuerpo Calloso , Feto/anomalías , Anomalías Múltiples/genética , Anencefalia/diagnóstico por imagen , Anencefalia/genética , Anoftalmos/diagnóstico por imagen , Anoftalmos/genética , Labio Leporino/diagnóstico por imagen , Labio Leporino/genética , Fisura del Paladar/diagnóstico por imagen , Fisura del Paladar/genética , Cuerpo Calloso/diagnóstico por imagen , Femenino , Genes Recesivos , Hernia Umbilical/diagnóstico por imagen , Hernia Umbilical/genética , Humanos , Masculino , Nariz/anomalías , Nariz/diagnóstico por imagen , Núcleo Familiar , Polidactilia/diagnóstico por imagen , Polidactilia/genética , Embarazo , Síndrome , Ultrasonografía Prenatal

RESUMEN

Haemophilia A and B are X-linked disorders which are due to a reduced activity of coagulation factor VIII or IX, respectively. Female carriers have a wide range of plasma concentration of factor VIII or factor IX, and may in rare cases have an affected phenotype. In order to investigate if this variation is related to X chromosome inactivation, we determined the X inactivation pattern in 31 haemophilia A and 15 haemophilia B carriers, using a PCR in the androgen receptor locus in blood DNA. Seven of the haemophilia A carriers and none of the haemophilia B carriers had a skewed pattern (> or =80:20). One of the skewed haemophilia A carriers had a low plasma concentration of factor VIII (0.15 U/ml), but the remaining 6 carriers did not differ in factor VIII concentration from that of carriers with a random X inactivation pattern. One carrier with a high factor VIII concentration (2.0 U/ml) did not have a skewed pattern. Similarly, for the haemophilia B carriers, there was no tendency to a more skewed X inactivation pattern in the carriers with low or high factor IX concentrations. In addition, we analysed a female with haemophilia B who was heterozygous for the mutation R180W in the factor IX gene. She had a random X chromosome inactivation pattern. We conclude that the wide range in plasma concentration of factor VIII and factor IX in haemophilia A and B carriers cannot in general be explained by the X chromosome inactivation pattern in peripheral blood cells.

Asunto(s)

Compensación de Dosificación (Genética) , Factor IX/metabolismo , Factor VIII/metabolismo , Hemofilia A/sangre , Hemofilia A/genética , Hemofilia B/sangre , Hemofilia B/genética , Adolescente , Adulto , Anciano , Niño , Factor IX/genética , Factor VIII/genética , Femenino , Haplotipos , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Mutación Puntual

RESUMEN

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.

Asunto(s)

Laminina/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos/genética , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Femenino , Genes Dominantes/genética , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Humanos , Lactante , Laminina/química , Laminina/metabolismo , Masculino , Persona de Mediana Edad , Distrofia Muscular de Emery-Dreifuss/metabolismo , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Linaje , Penetrancia , Polimorfismo Conformacional Retorcido-Simple , Estructura Terciaria de Proteína

RESUMEN

X inactivation makes females mosaics for 2 cell populations, usually with an approximate 1:1 distribution. Skewing of this distribution in peripheral blood cells is more common among elderly women. The depletion of hematopoietic stem cells followed by random differentiation may explain the acquired skewing with age. However, an animal model suggests that selection processes based on X-linked genetic factors are involved. We studied peripheral blood cells from 71 monozygotic twin pairs aged 73 to 93 years and from 33 centenarians, and we found that with age, 1 of the cell populations becomes predominant for most women. We also observed a strong tendency for the same cell line to become predominant in 2 co-twins. This suggests that X-linked genetic factors influence human hematopoietic stem cell kinetics. The fact that females have 2 cell lines with different potentials could be one of the reasons women live longer than men.

Asunto(s)

Ligamiento Genético , Células Madre Hematopoyéticas , Cromosoma X , Anciano , Anciano de 80 o más Años , Diferenciación Celular/genética , Compensación de Dosificación (Genética) , Femenino , Humanos , Cinética , Reacción en Cadena de la Polimerasa

RESUMEN

X-linked recessive myotubular myopathy (XLMTM) is a muscle disorder usually affecting newborn males. In the majority of cases, muscle weakness and hypotonia lead to a rapid demise at neonatal age. The responsible MTM1 gene is located in proximal Xq28. Heterozygous carriers are described as being asymptomatic but, in a few cases, mild facial weakness has been reported. We report a family in which a 39-year old female showed severe progressive muscle weakness. XLMTM was initially diagnosed in the male offspring of one of the patient's sisters. The patient, one of her sisters, and their mother were heterozygous carriers for a common MTM1 gene mutation. We found an extremely skewed X-inactivation pattern in the patient and, in the opposite direction, in her non-manifesting carrier mother, thus explaining her normal phenotype and indicating a possible inheritance of skewed X-inactivation. Linkage analysis excluded a possible involvement of the XIST locus at Xq13.

Asunto(s)

Compensación de Dosificación (Genética) , Enfermedades Musculares/genética , Cromosoma X/genética , Adulto , Anciano , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Ligamiento Genético , Haplotipos , Heterocigoto , Humanos , Masculino , Músculo Esquelético/patología , Enfermedades Musculares/patología , Mutación , Linaje , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas no Receptoras

RESUMEN

Clinical experience and molecular genetics have demonstrated several exceptions to Mendelian inheritance in man. Genomic imprinting is a mechanism that regulates expression or repression of genes according to their parental origin. The phenotypic expression of imprinted genes is therefore dependent on whether the gene was inherited from the father or the mother. More than 20 imprinted genes in man are recognized, and these genes tend to occur in clusters in the genome. The best characterized imprinted regions are the 15q11-13 region which involves Prader-Willi's syndrome and Angelman's syndrome and the 11p15 region involving Beckwith-Wiedemann's syndrome. The mechanism for disease expression in these two regions is discussed.

Asunto(s)

Síndrome de Angelman/genética , Síndrome de Beckwith-Wiedemann/genética , Impresión Genómica , Síndrome de Prader-Willi/genética , Animales , Aberraciones Cromosómicas , Mapeo Cromosómico , Cromosomas Humanos Par 15 , Regulación de la Expresión Génica , Humanos , Linaje

RESUMEN

In female mammals one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell types, cells with the maternal X as the active X chromosome, and cells with the paternal X as the active X chromosome. The process of X inactivation is random and permanent for each cell. A skewed X chromosome inactivation pattern may be defined as a pattern where the ratio between the two cell types is 80:20 or more. Skewed X inactivation may have several causes. Since X inactivation is a stochastic event, a skewed pattern may be the result of a chance occurrence. It may also be the result of genetic factors, or be the result of a selection leading to a growth advantage for one of the two cell types. A selection mechanism may be the reason for the increase in the frequency of skewed X inactivation found in normal elderly females. An important consequence of skewed X inactivation is the manifestation of X-linked disease in female carriers.

Asunto(s)

Compensación de Dosificación (Genética) , Cromosoma X , Adulto , Anciano , Anciano de 80 o más Años , División Celular/genética , Femenino , Ligamiento Genético , Humanos , Persona de Mediana Edad , Mosaicismo/genética

Asunto(s)

Compensación de Dosificación (Genética) , Hemofilia B/genética , Cromosoma X , Adulto , Femenino , Humanos , Linaje