Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal muscular atrophy (SMA) is an autosomal recessive disorder occurring at a rate of between 1/5,000 and 1/10,000 births in most European countries. The phenotype results from the degeneration of the anterior horn cells of the spinal cord, resulting in symmetrical muscle weakness and wasting. The disorder can be classified according to the severity of the disease and the age of onset into three major types. Two candidate SMA genes, NAIP and SMN, isolated from the 5q13 region, have been reported to be homozygously deleted in approximately 30% and >95% of SMA patients, respectively. Black SMA patients have been reported to have facial muscle weakness more commonly. This study aimed to determine the molecular basis of SMA in South African black SMA patients. The SMN gene was found to be homozygously deleted in 65.5% (19/29) of patients, significantly less frequently than in previous studies. Similarly, the NAIP gene was homozygously deleted in a smaller number, 14% (4/29) of patients; 47% (9/19) of SMN deletion patients appeared to have deletions of telomeric exon 7, but not exon 8. In at least six of these patients a gene conversion event has occurred. No detectable deletions were found in 35% (10/29) of patients. Haplotype analysis in the nondeletion patients, using six closely linked markers, provided no evidence for a founder mutation. No mutations were found in exons 3 and intron 6 through exon 8 by sequence analysis of these nondeletion patients. It is proposed that the differences in the SMA phenotype observed in black patients may in part be explained by a different molecular basis.
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PMID:Different molecular basis for spinal muscular atrophy in South African black patients. 1050 82

Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant, tubulo-interstitial nephropathy that causes renal salt wasting and end-stage renal failure in the fourth to seventh decade of life. MCKD1 was localized to chromosome 1q21. We demonstrated haplotype sharing and confirmed the telomeric border by a recombination of D1S2624 in a Belgian kindred. Since the causative gene has been elusive, high resolution haplotype analysis was performed in 16 kindreds. Clinical data and blood samples of 257 individuals (including 75 affected individuals) from 26 different kindreds were collected. Within the defined critical region mutational analysis of 37 genes (374 exons) in 23 MCKD1 patients was performed. In addition, for nine kindreds RT-PCR analysis for the sequenced genes was done to screen for mutations activating cryptic splice sites. We found consistency with the haplotype sharing hypothesis in an additional nine kindreds, detecting three different haplotype subsets shared within a region of 1.19 Mb. Mutational analysis of all 37 positional candidate genes revealed sequence variations in 3 different genes, AK000210, CCT3, and SCAMP3, that were segregating in each affected kindred and were not found in 96 healthy individuals, indicating, that a single responsible gene causing MCKD1 remains elusive. This may point to involvement of different genes within the MCKD1 critical region.
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PMID:Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing. 1673 48

Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.
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PMID:Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes. 1701 91

SMA is an autosomal recessive disorder that results in symmetrical muscle weakness and wasting due to degeneration of the anterior horns of the spinal cord. The gene for SMA, the survival motor neuron (SMN) gene is found on chromosome 5q13, in a region harbouring a 500kb duplication, resulting in two copies (a telomeric and a centromeric) of each of the genes found within the duplication. SMN1 is homozygously deleted in approximately 95% of patients worldwide. Results of the current study show that only 51% (42/92) of South African black SMA patients have homozygous deletions of the SMN1 gene. This frequency is significantly lower than observed in the South African white patient group and in other international populations. The pattern of deletions in the South African black patients is also significantly different. In order to elucidate the molecular basis of SMA in the black population, a dosage assay enabling the detection of SMN1 deletion heterozygotes was independently developed. This assay confirmed SMN1 heterozygosity in at least 70% of black non-deletion SMA patients. However, no second disease-causing mutation or a common chromosomal background for this mutation could be identified in these patients. The frequency of SMA in both the black and white population was also determined using the SMN1 gene dosage assay. Results showed that SMA is more common than previously thought with carrier rates of 1 in 50 and 1 in 23 and a predicted birth incidence of 1 in 3574 and 1 in 1945 in the black population and the white population, respectively. Development and incorporation of the SMN1 dosage assay into the molecular diagnostic service will increase the percentage of cases in which the diagnosis of SMA can be confirmed and allow preclinical and prenatal diagnosis. Further gene characterisation and functional studies would need to be performed in order to further define the molecular basis of SMA in the South African black population.
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PMID:The molecular basis of spinal muscular atrophy (SMA) in South African black patients. 1762 22

Progressive spinal muscular atrophy (SMA), the most prevalent hereditary lower motor neuron disease, is caused by mutations in the telomeric copy of the survival of motor neuron (SMN1) gene. Unlike other cells, lower motor neurons cannot tolerate low levels of smn protein. However, it is unclear as to the nature of the cell death involved. There is evidence that lower motor neurons undergo apoptosis in SMA, leading to muscle weakness and wasting. This study investigated whether SMN1 regulation in a motor neuron model affected indices of apoptotic cell death. Decreased smn expression in neuroblastoma hybrid (NSC-34) cell lines by small interfering RNA (siRNA) was demonstrated at the mRNA and protein level. Smn-depleted cells showed elevated caspase-3 activity, decreased cell viability and increased percentage of TUNEL positive cells. Conversely, NSC-34 cell smn overexpression by adenoviral gene transfer decreased staurosporine-induced caspase-3 elevation and mitigated induced cell toxicity as assessed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. However, increased smn expression by itself did not increase cell viability. These data suggest not only that decreased smn levels increase apoptosis in an in vitro model of SMA, but also that increased smn can protect against neural injury.
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PMID:Survival motor neuron protein regulates apoptosis in an in vitro model of spinal muscular atrophy. 1836 39