Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The survival motor neuron (SMN) gene is the putative disease gene for human spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by progressive degeneration of lower motor neurons. Two copies of the gene, centromeric and telomeric, are present in the same 5q13 chromosomal region in humans. However, only the telomeric gene is affected in SMA. The SMN gene(s) encode(s) a novel protein of unknown function. To gain insights into the role of SMN in neurons, we have identified the SMN gene ortholog in the rat, and investigated SMN expression in the CNS of rat, monkey and humans by immunocytochemistry and in situ hybridization experiments. Antibodies against the SMN amino-terminus specifically recognized a single protein identical to the in vitro translation products of human and rat SMN cDNAs. The SMN gene transcript and product were widely but unevenly expressed throughout cerebral and spinal cord areas. The SMN protein was localized mainly in the cytoplasm of specific neuronal systems, and it was particularly expressed in lower motor neurons of newborn and adult animals. Likewise, a strong hybridization signal was detected in lamina IX of the spinal ventral horn. These results support the relevance of SMN for the motor neuron function and the pathogenetic role of the SMN gene in the neuronal degeneration associated with SMA.
Hum Mol Genet 1997 Oct
PMID:Expression of the SMN gene, the spinal muscular atrophy determining gene, in the mammalian central nervous system. 930 77

High resolution respirometry in combination with the skinned fiber technique offers the possibility to study mitochondrial function routinely in small amounts of human muscle. During a period of 2 years, we investigated mitochondrial function in skeletal muscle tissue of 13 patients (average age = 5.8 years). In all of them, an open muscle biopsy was performed for diagnosis of their neuromuscular disorder. Mitochondrial oxidation rates were measured with a highly sensitive respirometer. Multiple substrate-inhibitor titration was applied for investigation of mitochondrial function. About 50 mg fibers were sufficient to obtain maximal respiratory rates for seven different substrates (pyruvate/malate, glutamate/malate, octanoylcarnitine/malate, palmitoylcarnitine/malate, succinate, durochinol and ascorbate/TMPD). Decreased respiration rates with reference to the wet weight of the permeabilized fiber could immediately be detected during the course of measurements. In 4 patients with mitochondrial encephalomyopathy (MEM) the respiration pattern indicated a specific mitochondrial enzyme defect, which was confirmed in every patient by measurements of the individual enzymes (one patient with PDHC deficiency, one with complex I deficiency and two patients with combined complex I and IV deficiency). In the 6 patients with spinal muscular atrophy (SMA) oxidation rates were found to be decreased of 23 +/- 5% of controls. The normalized respiration pattern was comparable to that of the controls indicating a decreased content of mitochondria in SMA muscle with normal functional properties. Also in the 3 patients with Duchenne muscular dystrophy (DMD) decreased oxidation rates (42 +/- 5%) were detected. In addition a low RCI (1.2) indicated a loose coupling of oxidative phosphorylation in the mitochondria of these patients. It is concluded that investigation of mitochondrial function in saponin skinned muscle fibers using high resolution respirometry in combination with multiple substrate titration offers a valuable tool for evaluation of mitochondrial alterations in muscle biopsies of children suffering from neuromuscular disorders.
Mol Cell Biochem 1997 Sep
PMID:High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders. 930 68

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.
Hum Mol Genet 1997 Dec
PMID:Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. 936 Oct 31

The neuronotoxicity of genes with expanded CAG repeats is most likely mediated by their respective polyglutamine (Gln)-expanded gene products. Gln- expanded portions of these products may be sufficient, or necessary, for pathogenesis. We tested whether a Gln-expanded human androgen receptor (AR) is structurally altered, so that it allows for the proteolytic generation of a potentially pathogenic portion that may be resistant to further degradation. We found, in vitro , that a Gln-expanded AR is more proteolytically resistant than normal, and that it yields a distinct set of Gln-expanded fragments even after extended proteolysis in the presence of 2 M urea. Furthermore, COS cells transfected with CAG-expanded AR cDNA generate an aberrant, nuclear-associated 75 kDa derivative containing the Gln-expanded tract. They are also twice as likely to die by 24 h apoptotically than those transfected with normal AR cDNA. Our data support the notion that an unconventional derivative of the Gln- expanded AR is a component of the proximate motor neuronopathic agent in spinobulbar muscular atrophy. They also focus attention on two ways in which neuronotoxic derivatives may originate from various Gln-expanded proteins: (i) generation of an unusual derivative that is pathogenic de novo ; and (ii) the toxic accumulation of a normal derivative because of an inability to dispose of it.
Hum Mol Genet 1998 Mar
PMID:Spinobulbar muscular atrophy: polyglutamine-expanded androgen receptor is proteolytically resistant in vitro and processed abnormally in transfected cells. 946 93

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the androgen receptor (AR). We have studied the mutant AR in an in vitro system, and find both aggregation and proteolytic processing of the AR protein to occur in a polyglutamine repeat length-dependent manner. In addition, we find the aberrant metabolism of expanded repeat AR to be coupled to cellular toxicity, indicating a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA.
Hum Mol Genet 1998 Apr
PMID:Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. 949 23

Severe muscle wasting is a characteristic feature of sepsis. We have previously established that the rate of protein synthesis in muscles composed of fast-twitch fibers is severely diminished in response to sepsis. The present studies investigate the biochemical reactions responsible for the decreased rate of protein synthesis using gastrocnemius from control and septic rats perfused in situ. Analysis of free ribosomal subunits indicated peptide-chain initiation was impaired by infection. To characterize biochemical reactions in the pathway of peptide-chain initiation affected, the effect of sepsis on the incorporation of initiator [35S]methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex was examined. Sepsis caused a 65% decrease in the binding of radiolabelled met-tRNA(imet) to the 40S initiation complex compared with controls. The binding of met-tRNA(met) to the 40S ribosome is regulated by eukaryotic initiation factor eIF-2B, whose activity can be modulated in part by the redox state of pyridine dinucleotides. The mean cytoplasmic NADH/NAD+ ratio was increased 2 fold in sepsis, while the NADPH/NADP+ ratio was unchanged. These findings identify the formation of the 40S initiation complex as a defect in the protein synthesis machinery during sepsis. The decreased formation of the 40S initiation complex in muscle could not be explained by changes in the cytoplasmic redox state.
Mol Cell Biochem 1998 Jan
PMID:Reduced 40S initiation complex formation in skeletal muscle during sepsis. 954 85

We have used gene targeting to create a mouse model of glycogen storage disease type II, a disease in which distinct clinical phenotypes present at different ages. As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice have markedly reduced mobility and strength. They grow normally, however, reach adulthood, remain fertile, and, as in the human adult disease, older mice accumulate glycogen in the diaphragm. By 8-9 months of age animals develop obvious muscle wasting and a weak, waddling gait. This model, therefore, recapitulates critical features of both the infantile and the adult forms of the disease at a pace suitable for the evaluation of enzyme or gene replacement. In contrast, in a second model, mutant mice with deletion of exon 6 (Delta6/Delta6), like the recently published acid alpha-glucosidase knockout with disruption of exon 13 (Bijvoet, A. G., van de Kamp, E. H., Kroos, M., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., and van der Ploeg, A. T. (1998) Hum. Mol. Genet. 7, 53-62), have unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathological changes. The genetic background of the mouse strains appears to contribute to the differences among the three models.
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PMID:Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. 966 92

Androgen effects mediated by the androgen receptor (AR) are essential for male reproductive development and virilization. Comparison of AR DNA coding sequence from five primate species, Homo sapiens (human), Pan troglodytes (chimpanzee), Papio hamadryas (baboon), Macaca fascicularis (macaque), and Eulemur fulvus collaris (collared brown lemur), supports their phylogeny with complete conservation of the DNA and steroid binding domain protein sequence. A linear increase in trinucleotide repeat expansion of homologous CAG and GGC sequences occurs in the NH2-terminal transcriptional activation region and is proportional to the time of species divergence. A serine phosphate/glutamine repeat interaction is observed where increasing CAG repeat length is associated with an increased rate of serine 94 phosphorylation. Disparity in the calculated and apparent molecular weight with CAG repeat expansion of an AR NH2-terminal fragment suggests self-aggregation with increasing glutamine repeat length into the pathological range. These results suggest that a CAG/glutamine repeat expanded during divergence of the higher primate species, which may have a direct effect on AR structure and support a common pathway in CAG trigenic diseases in the pathophysiology of neurodegeneration observed in X-linked spinal bulbar and muscular atrophy.
J Mol Evol 1998 Sep
PMID:Evolution of the primate androgen receptor: a structural basis for disease. 973 60

Childhood spinal muscular atrophy (SMA) is a common recessive autosomal disorder that results in degeneration of lower motor neurons. The identification of the disease gene, Survival of Motor Neuron (SMN), was a major advance in understanding the molecular basis underlying this devastating neuromuscular disease. This finding has greatly improved the genetic counselling of SMA families. Recently, biochemical studies demonstrated its involvement in the biogenesis of spliceosomal snRNPs, suggesting a critical role of SMN in RNA processing. Surprisingly, other studies showed a putative role of SMN in an anti-apoptotic pathway involving Bcl-2. The function of SMN protein is not fully understood. These observations emphasized the difficulty in elucidating the function of any novel protein. Therefore, multidisciplinary approaches are required to understand the pathogenesis of SMA.
Hum Mol Genet 1998
PMID:The role of the SMN gene in proximal spinal muscular atrophy. 973 73

After Duchenne muscular dystrophy, spinal muscular atrophy (SMA) is the most common severe neuromuscular disease in childhood. Since 1995, homozygous deletions in exon 7 of the survival motor neuron (SMN) gene have been described in >90-95% of SMA patients. However, the presence of a highly homologous SMN copy gene complicates the detection of exon 7 deletions. This paper describes the adjustment and evaluation of an established SMN exon 7 polymerase chain reaction (PCR) protocol at the single cell level, and the first preimplantation genetic diagnosis (PGD) of SMA with this PCR protocol. To determine PCR efficiency and allelic loss, 200 leukocytes of normal individuals, SMA carriers and patients, and 25 blastomeres were tested. The PCR efficiency of the SMN exon 7 and the adjacent copy gene sequence, tested in the leukocytes, were 90% and 91% respectively. No allelic loss was detected. One out of 25 blastomeres tested revealed a negative PCR signal for the SMN exon 7 sequence. All 25 showed the copy gene sequence. PGD of SMA was offered to a couple with an affected child homozygous for the SMN exon 7 deletion. After intracytoplasmic sperm injection, four and five embryos could be genotyped for the SMN exon 7 in two cycles respectively. After embryo transfer in the second PGD cycle an ongoing gemelli pregnancy was achieved. This study demonstrates that PGD for SMA is feasible when a previous child is homozygous for the SMN exon 7 deletion.
Mol Hum Reprod 1998 Sep
PMID:Preimplantation genetic diagnosis of spinal muscular atrophy. 978 49


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