RESUMEN
Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.
Asunto(s)
Desmina/genética , Proteínas de la Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Timopoyetinas/genética , Adolescente , Adulto , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Preescolar , Desmina/metabolismo , Femenino , Humanos , Laminina/genética , Laminina/metabolismo , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/patología , Miocardio/metabolismo , Miocardio/ultraestructura , Proteínas Nucleares , Linaje , Timopoyetinas/metabolismoAsunto(s)
Cardiomiopatías/diagnóstico por imagen , Distrofia Muscular de Duchenne/complicaciones , Adulto , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Diagnóstico Precoz , Ecocardiografía Doppler/métodos , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatología , Estudios ProspectivosRESUMEN
Several studies have recently highlighted the fact that the clinical involvement in females carrying a mutation in the dystrophin gene could be more frequent than usually thought, suggesting the need of a careful cardiac follow-up. Except for the classical chromosomal rearrangements, it was shown that a bias in the X chromosome inactivation process could be found in some affected females. We report two families illustrating different situations. The propositus of the first family, aged 32, presented with a proximal muscular weakness, increasing for three years, as well as elevated muscular enzymes in blood. Her brother suffered from classical Duchenne muscular dystrophy. Her mother was more severely affected, whereas her sister remained asymptomatic. A duplication of exons 3 to 7 of the dystrophin gene was found in all four patients. The affected carrier from the second family was a sporadic case. She has been suffering from proximal muscular weakness for six years. Muscle biopsy showed a mosaic pattern of the immunostaining using specific antidystrophin antibodies. A stop mutation was found in exon 52. Her ten year-old daughter, carrying the mutation, was asymptomatic. In both families, the inactivation profiles were in accordance with the clinical presentation. We discuss the different mechanisms that may lead to the inactivation bias in these patients, as well as the advantage and limits of using the X chromosome inactivation test as a tool for diagnosis and prognosis purpose in symptomatic carriers for dystrophinopathies.
Asunto(s)
Cromosomas Humanos X/genética , Distrofina/genética , Silenciador del Gen , Distrofias Musculares/genética , Adolescente , Adulto , Codón de Terminación/genética , Exones , Familia , Femenino , Heterocigoto , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/genética , Músculo Esquelético/patología , Distrofias Musculares/patología , Distrofia Muscular de Duchenne/genética , LinajeRESUMEN
We report a 6-year-old female patient presenting with a sudden and severe single episode of rhabdomyolysis in which screening for a metabolic disorder was negative. Four months after the episode a muscle biopsy was performed and showed a mild pattern of necrosis/regeneration. Upon immunofluorescence, a mosaic pattern of dystrophin deficiency was found, and in the dystrophin deficient muscle fibres, the four proteins of the sarcoglycan complex were also lacking. Genetic analysis showed a duplication of exons 3 to 17 on one X-chromosome of the proband, but not on the mother's X-chromosome. A clearly skewed X-inactivation (85% of the defective X being active) was found and is consistent with the patient being symptomatic. To our knowledge, a spontaneous rhabdomyolysis in a female Duchenne muscular dystrophy carrier has never been reported.
Asunto(s)
Compensación de Dosificación (Genética) , Distrofina/genética , Genes Duplicados , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Biopsia , Niño , Femenino , Heterocigoto , Humanos , Distrofia Muscular de Duchenne/metabolismo , Rabdomiólisis/genética , Rabdomiólisis/metabolismo , Rabdomiólisis/patología , Cromosoma XRESUMEN
AIM: To describe the clinical variability of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) with cardiac involvement in a four-generation family with a novel mutation in the STA gene. METHODS: Clinical data were provided for 4 affected males and a female carrier. The Western blot analysis of emerin was performed on lymphoblastoid cell lines and followed by sequencing of the emerin gene. RESULTS: A thymine insertion at nucleotide 417 in exon 2, resulting in a frameshift with a premature stop codon at position 62 and absence of functional protein, was found in one of the three available patients. In ten-year-old proband's dizygotic twin-nephews the intermittent first-degree A-V block, atrial and ventricular ectopy, atrial runs, and exit sinus block were found, although the echocardiographic findings were normal. One of the twins also had short episodes of atrial fibrillation, idioventricular rhythm, and junctional rhythm. CONCLUSION: Cardiac abnormalities in the proband's ten-year-old dizygotic twins without evident clinical features suggestive of EDMD were remarkable in contrast to the oldest patient in the family, who lived to the age of 63 without a pacemaker, and to the proband who had a very early onset of muscle wasting and weakness, and a pacemaker implantation at the age of 27. This striking intra-familial variability in cardiac involvement associated with specific null mutation (417 ins T) has practical early diagnostic and possibly preventive implications. It also points at genetic and environmental factors as causes of clinical features in X-EDMD.
Asunto(s)
Distrofia Muscular de Emery-Dreifuss/genética , Adulto , Anciano , Western Blotting , Portador Sano , Codón , Análisis Mutacional de ADN , Exones , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas Nucleares , Linaje , Fenotipo , Timopoyetinas/genéticaRESUMEN
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.
Asunto(s)
Genes Dominantes/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación Missense , Proteínas Nucleares/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Biopsia , Fenómenos Fisiológicos Cardiovasculares , Niño , Contractura/diagnóstico , Contractura/fisiopatología , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Genotipo , Corazón/fisiopatología , Humanos , Lamina Tipo A , Laminas , Masculino , Persona de Mediana Edad , Debilidad Muscular/diagnóstico , Debilidad Muscular/fisiopatología , Atrofia Muscular/diagnóstico , Atrofia Muscular/fisiopatología , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Miocardio/patología , Linaje , Fenotipo , Examen FísicoRESUMEN
X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited mild myopathy. We have used 32 polymorphic markers spanning the entire X chromosome to exclude most of the chromosome except the Xq28 region in a large XMEA family. Using three additional families for linkage analysis, we have obtained a significant two-point lod score with marker DXS1183 (Z = 2.69 at theta = 0). Multipoint linkage analysis confirmed the assignment of the disease locus with a maximal lod score of 2.74 obtained at recombination fraction zero. Linkage of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct sequencing of the emerin gene in three of our families.
Asunto(s)
Enfermedades Musculares/genética , Cromosoma X/genética , Biopsia , Mapeo Cromosómico , ADN/química , ADN/genética , Salud de la Familia , Femenino , Ligamiento Genético , Haplotipos , Humanos , Escala de Lod , Masculino , Proteínas de la Membrana/genética , Repeticiones de Microsatélite , Músculo Esquelético/patología , Enfermedades Musculares/patología , Mutación , Proteínas Nucleares , Linaje , Análisis de Secuencia de ADN , Timopoyetinas/genéticaRESUMEN
Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.
Asunto(s)
Glándulas Suprarrenales/fisiopatología , Proteínas de Unión al ADN/genética , Hipogonadismo/genética , Mutación , Receptores de Ácido Retinoico/genética , Proteínas Represoras , Factores de Transcripción/genética , Adulto , Edad de Inicio , Animales , Receptor Nuclear Huérfano DAX-1 , Humanos , Hipogonadismo/fisiopatología , Masculino , Ratones , Ratones NoqueadosRESUMEN
Emery-Dreifuss muscular dystrophy is an X-linked neuromuscular disorder caused by defects in the STA gene on Xq28, which codes for a nuclear protein named emerin. Affected patients usually present in early adolescence with scapulo-peroneal muscle weakness and wasting, and contractures of the tendo Achilles, elbows and paraspinal muscles, resulting in spine rigidity. We present here a case of Emery-Dreifuss muscular dystrophy with an unusually severe, early presentation. He presented at 2.5 years with predominantly proximal weakness and mild equinovarus deformity of the right foot. Serum creatine kinase activity was elevated (1994 IU/I) and a muscle biopsy at the age of 4 years showed marked dystrophic abnormalities. Normal expression of dystrophin, and no detectable deletion in the corresponding gene, excluded a diagnosis of Duchenne muscular dystrophy. Similarly, normal expression of alpha-sarcoglycan made a limb-girdle muscular dystrophy caused by a defect in a sarcoglycan unlikely. Several years later, examination of the proband's maternal cousin, aged 14 years, suggested Emery-Dreifuss muscular dystrophy. This was confirmed in both affected boys by the absence of emerin in muscle and leucocytes, and identification of a mutation in exon 4 of the STA gene. Carrier status in both mothers was also confirmed by mutational and protein analysis. Emery-Dreifuss muscular dystrophy should therefore be considered in the differential diagnosis of cases of early onset muscular dystrophy, even in the absence of the typical clinical features.
Asunto(s)
Ligamiento Genético , Distrofias Musculares/genética , Cromosoma X , Edad de Inicio , Biopsia , Preescolar , Diagnóstico Diferencial , Humanos , Leucocitos/patología , Masculino , Proteínas de la Membrana/genética , Músculos/patología , Distrofias Musculares/clasificación , Distrofias Musculares/patología , Distrofia Muscular de Emery-Dreifuss , Mutación , Proteínas Nucleares , Linaje , Piel/patología , Timopoyetinas/genéticaRESUMEN
Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutations in the X-linked emerin gene, while three showed evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation. An in-frame deletion of six amino acids from the C-terminal transmembrane helix caused almost complete absence of emerin from muscle with no localization to the nuclear membrane, although mRNA levels were normal. This shows that mutant emerin proteins are unstable if they are unable to integrate into a membrane. A 22 bp deletion in the promoter region was expected to result in reduced emerin production, but normal amounts of emerin of normal size were found in leucocytes and lymphoblastoid cell lines. This shows that DNA analysis is necessary to exclude emerin mutations in suspected X-linked EDMD. Emerin levels in female carriers often deviated from the expected 50% and this was due, in at least two families, to skewed emerin mRNA expression from the normal and mutated alleles. In one family with a novel deletion of the last three exons of the emerin gene, a carrier had a cardiomyopathy and very low emerin levels (<5% of normal) due to skewed X-inactivation. In the three autosomal cases of EDMD, emerin was normal on western blots of blood cells, which suggests that autosomal EDMD is not caused by indirect reduction of emerin levels.
Asunto(s)
Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Distrofias Musculares/genética , Mutación/genética , Timopoyetinas/biosíntesis , Timopoyetinas/genética , Adolescente , Adulto , Línea Celular Transformada , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Linfocitos , Masculino , Persona de Mediana Edad , Distrofias Musculares/metabolismo , Distrofia Muscular de Emery-Dreifuss , Proteínas Nucleares , Linaje , Cromosoma X/genéticaRESUMEN
Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectodermal involvement, demonstrates phenotypic overlap in some patients with Noonan syndrome (NS), ultimately resulting in the so-called neurofibromatosis-Noonan syndrome (NF-NS). A strong association of the two phenotypic traits was recently illustrated by a four-generation family, although NF1 and NS were eventually demonstrated to segregate independently on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J Med Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial association. Using the protein truncation assay, a nonsense mutation (C2446T-->R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specifying region of the gene. R816X creates a recognition site for endonuclease HphI, absent in 2 individuals with NS only. Screening 184 unrelated NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of genotype-phenotype correlation in these individuals, clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.
Asunto(s)
Neurofibromatosis 1/genética , Síndrome de Noonan/genética , Mutación Puntual/genética , Análisis Mutacional de ADN , Desoxirribonucleasas de Localización Especificada Tipo II , Femenino , Humanos , Masculino , Linaje , Fenotipo , Eliminación de SecuenciaRESUMEN
We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH2 domains of dystrophin were almost normal. The immunoreactions for alpha-sarcoglycan, gamma-sarcoglycan and beta-dystroglycan were normal. In the five male patients of this family with increased serum creatine kinase levels (from x8 to x50), mass spectrometry screening of the urine revealed a large increase in glycerol elimination which was quantified by enzymatic assay (from x14 to x39). An in-frame deletion of the dystrophin gene (exons 13-29) was found in the same five males and in three carrier females. All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278. These findings indicate that the two mutations cosegregate on the same chromosome in this family. This is the first reported case of two physically independent mutations, within the DMD and GK genes, which are contiguous but several hundred kilobases apart.
Asunto(s)
Distrofina/genética , Ligamiento Genético , Glicerol Quinasa/genética , Distrofias Musculares/genética , Mutación Puntual , Cromosoma X , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico , Femenino , Eliminación de Gen , Humanos , Masculino , Linaje , SíndromeRESUMEN
X-linked non-specific mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. The genetic and phenotypic heterogeneity exclude any possibility of pooling families and, therefore, of fine-mapping the related disease genes. In order to identify genomic critical regions involved in the MRX condition assigned to Xp21.3-22.1 region, we have implemented the PCR screening of non fragile X MR patients for the presence of deletions in this region. The amplification by PCR of 12 markers located between POLA and DXS704 using genomic DNA from 192 MR males led to the identification, in a 9 year old mentally retarded boy, of a microdeletion which extends from DXS1202 to DXS1065. None of the known genes, POLA, MAGE genes cluster, DAX1, GK and DMD, that map in the Xp21.3-22.1 region is affected by this deletion. This approach, which could easily be applied to several other MRX loci, allowed not only a confirmation of the presence of a potential locus in Xp21.3-22.1 involved in non-specific mental retardation, but also a better definition of the genomic critical region corresponding to this locus.
Asunto(s)
Deleción Cromosómica , Ligamiento Genético , Discapacidad Intelectual/genética , Lugares Marcados de Secuencia , Cromosoma X/genética , Niño , Mapeo Cromosómico , ADN/análisis , Marcadores Genéticos , Humanos , Masculino , Reacción en Cadena de la Polimerasa/métodosRESUMEN
A 25 year old woman, without family history of muscular dystrophy, had had an isolated lower limb hypertrophy since infancy and later experienced exercise-induced myalgia. Genomic DNA analysis showed a deletion of exons 45 to 52 of the dystrophin gene. Uncommon phenotypes of dystrophinopathies and consequences in genetic counselling in women are emphasised.
Asunto(s)
Distrofina/genética , Ejercicio Físico , Pierna , Enfermedades Musculares/genética , Adulto , Femenino , Humanos , Hipertrofia , Distrofias Musculares/genéticaRESUMEN
Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD). This is a Duchenne-like disease affecting both males and females first described in Tunisian families. Adhalin deficiency has been found in SCARMD patients from North Africa Europe, Brazil, Japan and North America (SLR & KPC, unpublished data). The disease was initially linked to an unidentified gene on chromosome 13 in families from North Africa, and to the adhalin gene itself on chromosome 17q in one French family in which missense mutations were identified. Thus there are two kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin (primary adhalinopathies), and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13. We have examined the importance of primary adhalinopathies among myopathies with adhalin deficiency, and describe several additional mutations (null and missense) in the adhalin gene in 10 new families from Europe and North Africa. Disease severity varies in age of onset and rate of progression, and patients with null mutations are the most severely affected.
Asunto(s)
Proteínas del Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Proteínas del Citoesqueleto/análisis , Proteínas del Citoesqueleto/deficiencia , Distrofina/análisis , Distrofina/genética , Femenino , Genes Recesivos , Humanos , Masculino , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/deficiencia , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Puntual , Conformación Proteica , Sarcoglicanos , Índice de Severidad de la EnfermedadRESUMEN
Adrenal hypoplasia congenita (AHC) is an X-linked disorder characterized by primary adrenal insufficiency. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder but is thought not to be caused by the low adrenal androgen levels due to adrenal hypoplasia. It is uncertain whether there are two distinct yet physically linked genes responsible for AHC and HHG or a single gene responsible for both diseases. AHC can occur as a part of a contiguous deletion syndrome together with Duchenne muscular dystrophy (DMD) and/or glycerol kinase deficiency (GKD). From the analysis of deletions, the following gene order has been deduced: Xpter-AHC-GKD-DMD-cen. An AHC critical region of 200-500 kilobases has been defined by physical mapping and partially overlaps with a 160-kilobase dosage-sensitive sex (DSS) reversal critical region. The DAX-1 (DSS-AHC critical region on the X, gene 1) gene was isolated and found to encode a new member of the nuclear hormone receptor family. Here we report that DAX-1 is deleted in 14 patients and point mutations were found in the coding region in DNA from 12 unrelated individuals. All AHC patients over 14 years old and with only point mutations in DAX-1 were also diagnosed with HHG, confirming that the DAX-1 gene is responsible for both X-linked AHC and HHG. But in four sporadic cases and a single familial case, no point mutations were found, suggesting genetic heterogeneity or differential expression of DAX-1.
Asunto(s)
Insuficiencia Suprarrenal/congénito , Insuficiencia Suprarrenal/genética , Proteínas de Unión al ADN/genética , Hipogonadismo/genética , Mutación Puntual , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Ácido Retinoico/genética , Proteínas Represoras , Factores de Transcripción/genética , Cromosoma X , Secuencia de Bases , Niño , Preescolar , Receptor Nuclear Huérfano DAX-1 , ADN , Ligamiento Genético , Humanos , Lactante , Recién Nacido , Datos de Secuencia Molecular , Mapeo RestrictivoRESUMEN
A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in the DMD gene and discordant for the clinical manifestations of Duchenne muscular dystrophy, were analyzed by molecular studies, in situ hybridization, and methylation pattern of X chromosomes to search for opposite X inactivation as an explanation of their clinical discordance. Results in lymphocytes and skin fibroblast cell lines suggest a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternal deleted X chromosome preferentially active in the affected twin. A review shows that MZ female twins discordant for X-linked diseases are not uncommon. Twinning and X inactivation may be interrelated and could explain the female twins discordant for X-linked traits.
Asunto(s)
Enfermedades en Gemelos/genética , Compensación de Dosificación (Genética) , Distrofias Musculares/genética , Gemelos Monocigóticos , Secuencia de Bases , Niño , Distrofina/análisis , Distrofina/biosíntesis , Distrofina/genética , Femenino , Regulación de la Expresión Génica , Humanos , Hibridación in Situ , Datos de Secuencia Molecular , Linaje , Eliminación de SecuenciaRESUMEN
A girl with severe Becker muscular dystrophy and apparently normal chromosomes had a heterozygous deletion for exons 51, 52, and 53 of the dystrophin gene. This deletion was transmitted by her mother, who was unaffected. To differentiate the normal and the deleted X chromosomes, fluorescence in situ hybridization (FISH) was applied to metaphase chromosomes, using probes for both exons 51 and 52, which are only 388 and 113 base pairs long, respectively. FISH signals were observed in one or both chromatids of one chromosome, but never on both chromosomes, suggesting the lack of hybridization on the deleted X chromosome. Using 5-bromodeoxyuridine incorporation to differentiate the late (inactive) and the early replicating (active) X chromosomes, 77% of the signals were observed on the active X chromosomes in the mother. This percentage was only 18% in the daughter, suggesting that skewed inactivation of the X chromosomes was responsible for the phenotypic differences.
Asunto(s)
Deleción Cromosómica , Compensación de Dosificación (Genética) , Distrofina/genética , Distrofias Musculares/genética , Aberraciones Cromosómicas Sexuales/genética , Cromosoma X , Adolescente , Adulto , Western Blotting , Citogenética , ADN/análisis , Distrofina/metabolismo , Exones/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Músculos/metabolismo , Distrofias Musculares/metabolismo , FenotipoRESUMEN
Hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and PC with myotonia permanens are closely related muscle disorders of genetic origin due to allelic mutations in the muscle sodium channel gene, SCN4A. Seven families of French origin with hyperPP were studied. Five of these had the Thr704Met mutation, but 2 families, genetically linked to SCN4A, failed to show any of the known mutations of SCN4A. Correlations between the phenotype and the genotype were made for patients with the Thr704Met mutation. All 12 patients over 30 years old with the Thr704Met mutation presented muscle weakness due to degeneration of muscle fibers in addition to periodic paralysis. Only approximately 12.5% of patients with the Thr704Met mutation presented with clinical myotonia and about 50% with hyperkalemia. One family with PC displayed the Gly1306Val mutation with a phenotype similar to the one already reported for this mutation. Five families with either PC or PC with myotonia permanens had the Thr1313Met mutation indicating that the severity of myotonia and its permanence were variable. Two mutations of SCN4A were found to be predominant in these 13 families: the Thr704Met and the Thr1313Met mutations. Only 2 families with the Thr704Met mutation and 3 families with the Thr1313Met shared the same SCN4A haplotype determined with intragenic dinucleotide repeats. Recurrent mutations of SCN4A may contribute to the predominance of these two mutations in the French population.
Asunto(s)
Hiperpotasemia/genética , Miotonía Congénita/genética , Parálisis Periódicas Familiares/genética , Mutación Puntual , Canales de Sodio/genética , Adolescente , Secuencia de Bases , Distribución de Chi-Cuadrado , Niño , Preescolar , Análisis Mutacional de ADN , Cartilla de ADN , ADN de Cadena Simple/análisis , Femenino , Francia , Frecuencia de los Genes , Ligamiento Genético , Genotipo , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.