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At least 991 records · Page 55Linked to original sources
PubMed2002

Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?

Spinal muscular atrophy (SMA), the most common hereditary motor neuron disease in children and young adults is caused by mutations in the telomeric survival motor neuron (SMN1) gene. The human genome, in contrast to mouse, contains a second SMN gene (SMN2) which codes for a gene product which is alternatively spliced at the C-terminus, but also gives rise to low levels of full-length SMN protein. The reason why reduced levels of the ubiquitously expressed SMN protein lead to specific motor neuron degeneration without affecting other cell types is still not understood. Using yeast two-hybrid techniques, we identified hnRNP-R and the highly related gry-rbp/hnRNP-Q as novel SMN interaction partners. These proteins have previously been identified in the context of RNA processing, in particular mRNA editing, transport and splicing. hnRNP-R and gry-rbp/hnRNP-Q interact with wild-type Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins are widely expressed and developmentally regulated with expression peaking at E19 in mouse spinal cord. hnRNP-R binds RNA through its RNA recognition motif domains. Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment. Thus, this finding could provide a key to understand a motor neuron-specific Smn function in SMA.

Amino Acid Sequence↗
PubMed1999

Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.

Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations.

Cyclic AMP Response Element-Binding Protein↗
PubMed1991

In situ hybridization of two markers closely flanking the spinal muscular atrophy gene to 5q12----q13.3.

In order to refine the physical location of the p105-153Ra and M4 probes which closely flank the spinal muscular atrophy gene (SMA) on human chromosome 5q, in situ hybridization has been carried out on prometaphase chromosomes. Our results demonstrate that the disease gene is located between the 5q12----q13.1 and 5q13.3 bands. The present study will hopefully contribute to microdissection of the chromosomal region of the SMA gene.

Child↗
PubMed1986

Unusual pedigree patterns in seven families with spinal muscular atrophy; further evidence for the allelic model hypothesis.

Clinical and genetic findings are presented in 18 patients, from 7 pedigrees with different types of spinal muscular atrophy (SMA). The SMA diagnosis was based on EMG and muscle biopsy findings. All 7 pedigrees show an unusual genetic pattern, not consistent with simple autosomal recessive inheritance. Furthermore, in 6 of the 7 pedigrees different types of SMA were present within each pedigree. Our findings can be explained by an extension of a multiple alleles hypothesis originally described by Becker in 1964.

Alleles↗
PubMed1993

Lack of cervical paraspinal muscle involvement in juvenile distal spinal muscular atrophy: an electromyographic study on 15 cases.

Electromyography (EMG) of the lower cervical paraspinal muscles was performed in 15 young Chinese males with distal spinal muscular atrophy of the upper extremities. The lack of fibrillation and positive sharp waves in all patients, both in early or active and chronic or steady stages, did not correlate with the EMG status in the affected upper extremity on the same side. This finding is in striking contrast with that in amyotrophic lateral sclerosis.

Adolescent↗
PubMed1994

Monoamine metabolites in the cerebrospinal fluid in infantile spinal muscular atrophy.

Analyses of tryptophan and tyrosine metabolites in cerebrospinal fluid were performed to examine an abnormality of the monoamine neurone system in severe infantile spinal muscular atrophy (SMA type I). The levels of 5-hydroxyindoleacetic acid and homovanillic acid were significantly lower than those in controls. Decreases in the concentration of 5-hydroxyindoleacetic acid and kynurenine seemed to be related to the severity of SMA type I. These results suggest that the monoamine neurone system may play a role in the pathophysiology of SMA type I.

Biogenic Monoamines↗
PubMed1979

Mitochondrial abnormalities of late motor neuron degeneration following poliomyelitis and other neurogenic muscular atrophies.

A case of late motor neuron degeneration following poliomyelitis with abnormal mitochondria in muscle fibers is presented with two additional cases of systemic neurogenic muscular atrophy (Charcot-Marie-Tooth disease). Muscle biopsy revealed a neurogenic pattern of variable severity in all cases. Subsarcolemmal zones of hyperactivity and hyperpositive intermyofibrillar collections of granular material present in a variable proportion of type I fibers were demonstrated by oxidative enzymes. Ultrastructurally they corresponded to abnormal mitochondria, with paracrystalline inclusions in one case. The finding is discussed in the light of the previous literature on mitochondrial myopathies. Mitochondrial alterations are not specific and their significance in neurogenic conditions is debated.

Adolescent↗
PubMed1991

Becker muscular dystrophy or spinal muscular atrophy?--Dystrophin studies resolve conflicting results of electromyography and muscle biopsy.

We studied a 29-year-old man with slowly progressive proximal leg weakness, calf hypertrophy, and high serum levels of creatine kinase activity. Clinically, it was not possible to identify his as a sporadic instance of Becker muscular dystrophy (BMD) or one of spinal muscular atrophy. The problem arose because electromyography and elevated creatine kinase suggested a myopathy whereas changes in the muscle biopsy resembled a neurogenic disorder. The diagnosis of BMD was made by DNA analysis which detected a deletion at Xp21 and by immunoelectrophoresis and immunohistochemical tests that identified an abnormal form of gene product, dystrophin. These studies were important for genetic counselling, identifying an X-linked disease instead of one that is autosomal recessive.

Adult↗
PubMed1997

The reduction of androgen receptor mRNA in motoneurons of X-linked spinal and bulbar muscular atrophy.

We examined the expression level of androgen receptor (AR) messenger RNA (mRNA) in the motoneurons from patients with X-linked spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) using in situ hybridization. Although AR mRNA was detected in motoneurons from the SBMA patient, the expression level was lower than that from the patients with ALS, despite similar loss of motoneurons. The expression level of AR mRNA in the dorsal nucleus of Clarke from the patient with SBMA was similar to that in the patients with ALS, suggesting that the qualities of the mRNA were similar in each spinal cord sample and that AR mRNA was uniquely reduced in the motoneurons of the SBMA patient. Decreased levels of AR mRNA may be involved in the pathogenesis of SBMA resulting in degeneration of motoneurons.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

Analysis of the SMN and NAIP genes in slovak spinal muscular atrophy patients.

We identified homozygous absence of exon 7 of the telomeric copy of the survival motor neuron gene (telSMN) in 88.4% (38/43) of spinal muscular atrophy (SMA) patients from Slovakia. Additional deletions within the neuronal apoptosis inhibitory protein (NAIP) gene were found in 38.5% of type I, 12.5% of type II and never in type III SMA patients. Neither the SMN nor the NAIP gene was deleted in 81 healthy relatives and 25 controls tested. In one family, pseudodominant inheritance was identified. Both the type III SMA father and type II SMA son carried the homozygous deletion of the telSMN gene. One SMA I patient showed an SMN hybrid gene, probably created by intrachromosomal deletion. In two haploidentical type II SMA sibs, the telSMN exon 7 was absent on one chromosome, while the other carried an A-->G transition 96 bp upstream of exon 7 of the telSMN gene, a potential disease-causing mutation in these patients.

Cyclic AMP Response Element-Binding Protein↗
PubMed1993

Sleep related breathing patterns in patients with spinal muscular atrophy.

A clinical and polygraphic study of nocturnal sleep was performed in 8 (4 males, 4 females; age range 10-37 years) patients with spinal muscular atrophy, whose baseline respiratory function assessment during wakefulness showed restrictive ventilatory syndrome but blood-gas tension within normal limits. No patient reported any significant sleep complaint suggestive of sleep-disordered breathing. However, in 4 patients HbSaO2 desaturations below 90% (HbSaO2 nadir 68%) were detected during nocturnal polysomnography. The HbSaO2 desaturations occurred during brief central apneas or hypopneas, mainly during REM sleep, the apnoea hypopnea index being within normal limits in all cases. The data suggest that nocturnal polysomnography can detect otherwise clinically silent hypoxemia in SMA patients without any predisposing factor to sleep-disordered breathing other than their illness and still showing normal blood-gas tensions during wakefulness. Further studies are needed to determine the long-term evolution and the prognostic significance of nocturnal hypoxemia in these patients.

Adolescent↗
PubMed1999

Application of DNA-based tests for diagnosis of spinal muscular atrophy in Saudi Arabia.

We examined the deletion of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in patients with spinal muscular atrophy (SMA) using polymerase chain reaction followed by restriction site assay methods. The study included 16 Saudi patients (9 SMA type I and 7 SMA type II) and 6 healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene, and exon 5 of the NAIP gene were found in all SMA type I patients. Exons 7 and 8 of telomeric SMN were deleted in all SMA type II patients. However, exon 5 of NAIP was deleted in three of the seven cases. All control volunteers and all family members of the patients had normal SMN and NAIP. The incidence of NAIP deletion was higher in the more severe SMA cases and the dual deletion of the SMN and NAIP genes was more common in Saudi SMA type I patients compared with patients of other ethnic groups.

Case-Control Studies↗
PubMed1987

Cell adhesion molecule N-CAM is expressed by denervated myofibres in Werdnig-Hoffman and Kugelberg-Welander type spinal muscular atrophies.

Immunocytochemical analysis utilising antibody to neural cell adhesion molecule (N-CAM) was carried out on skeletal muscle biopsies from patients with childhood spinal muscular atrophy. Children with both Werdnig-Hoffmann and Kugelberg-Welander disease showed positive N-CAM reactivity. There were however differences in the N-CAM expression profiles in these two sets of patients. All myofibres were positive for N-CAM in the Werdnig-Hoffmann patients. This included both the normal sized fibres and the atrophic fibres. In contrast only the atrophic fibres were positive in the Kugelberg-Welander patients. No reactivity was found associated with the large hypertrophic fibres. It is likely that in the Werdnig-Hoffmann patients the positive N-CAM reactivity reflects unstable innervation of myofibres that had been previously innervated. A similar mechanism may operate in the Kugelberg-Welander patients, but the innervation of the hypertrophic fibres is more stable as they are able to repress N-CAM expression. These results contrast with a lack of N-CAM expression found previously on muscle biopsies from adults with denervation disease.

Antigens, Surface↗
PubMed2004

An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy.

SMN1 and SMN2 represent the two nearly identical copies of the survival of motor neuron gene in humans. The most frequent cause of spinal muscular atrophy (SMA) is loss of SMN1 accompanied by the inability of SMN2 to compensate due to an inhibitory mutation at position 6 in exon 7 (C6U) that causes exon 7 exclusion. How this single exonic nucleotide regulates exon 7 recognition has been of major interest. Based on score matrices and in vitro assays, abrogation of an exonic splicing enhancer (ESE) associated with SF2/ASF has been considered as the cause of exon 7 exclusion. However, a recent report supports the creation of an exonic splicing silencer (ESS) associated with hnRNP A1 as the determining factor for exon 7 exclusion. Here we show that C6U strengthens an inhibitory context that covers a larger sequence than the hnRNP A1 binding site. The inhibitory context can also be strengthened by the addition of a G residue at the first position of exon 7 in SMN1, promoting exon 7 skipping despite the presence of SF2/ASF binding site. Through in vivo selection and a series of mutations we demonstrate that the strengthening of the extended inhibitory context at the 5' end of exon 7 is exercised through overlapping sequence motifs that collaborate to regulate exon usage.

Amino Acid Motifs↗
PubMed1993

Formation of primary and secondary myotubes in aneural muscles in the mouse mutant peroneal muscular atrophy.

The role of motor innervation in supporting and regulating muscle development was studied using aneural muscles in the hindlimb of the mouse mutant peroneal muscular atrophy (pma). This is a single-locus autosomal mutation where homozygous animals lack the common peroneal nerve, so that muscles in the anterolateral compartment of the lower leg develop entirely without innervation. In adults, these muscles are extremely atrophied, and the mice display a clubfoot deformity. The mutant animals provide a preparation in which aspects of muscle formation can be studied in muscles that have never been exposed to direct contact with somatic motor or sensory axons, without pharmacological or surgical intervention. Using quantitative electron microscopy, we found that normal numbers of primary myotubes formed in aneural pma EDL muscles, but a greater than normal proportion degenerated during the first 2 days after their formation. Secondary myotubes appeared at their normal time and position within the muscle, initially in normal numbers, so that the ratio of secondary to primary myotubes initially was greater in pma than in CF1 control strain mice. No abnormalities in ultrastructure were seen until the time of birth, when retardation in development was obvious, together with invading macrophages and degenerating myofibres. The results show that secondary myotube formation in the mouse, as in the chick (B. J. Fredette and L. T. Landmesser, Dev. Biol. 143, 19-35, 1991) is not directly dependent on innervation. In control muscles, secondary myotubes first form in the vicinity of endplates on primary myotubes. No aggregations of ACh receptors or acetylcholinesterase were present in the aneural muscles, showing that these are neurally induced in the mouse, but secondary myotubes formed in their normal position indicating that positional information related to endplate formation is present in aneural muscles.

Acetylcholinesterase↗
PubMed2003

Neuropathological analysis in spinal muscular atrophy type II.

We performed a neuropathological analysis, including in situ nick end labeling (ISEL) and immunohistochemistry, of two cases of clinicogenetically confirmed infantile spinal muscular atrophy (SMA) type II. Both cases showed severe reduction of the motor neurons and gliosis in the spinal cord and brain stem, although the occurrences of central chromatolysis and ballooned neurons were not frequent. Clark's and lateral thalamic nuclei, which are usually altered in SMA type I, were spared, whereas Betz cells in the precentral gyrus and large myelinated fibers in the lateral funiculus were reduced in number. Regarding apoptosis, only the younger case demonstrated a few ISEL-positive nuclei in the dorsal horn, with reduced Bcl-x expression level in the Purkinje cells. Unlike SMA type I, the expression of neurofilaments was not disturbed and the reduction in synaptophysin expression level in the anterior horn was mild. An oxidative stress-related product was deposited in atrophic motor neurons in the spinal cord, and neurons with nuclei immunoreactive for 8-hydroxy-2'-deoxyguanosine were found in the lateral thalamus. In contrast, the expression of glial glutamate transporters was not altered. These data suggest that oxidative stress and, to a lesser extent, apoptotic cell death, but not disturbed neurofilament metabolism or excitotoxicity, may be involved in neurodegeneration in SMA type II.

Adult↗
PubMed1974

Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity.

Measurements of motor nerve conduction velocity are reported in 88 subjects from 20 families in which a clinical diagnosis of peroneal muscular atrophy had been made in the index cases. The values display a bimodal distribution. The majority of cases show a substantially reduced conduction velocity, a smaller group displaying velocities within the normal range or only slightly decreased. This difference was demonstrated to have a genetic basis.

Adolescent↗
PubMedDate not supplied

Lack of serum neutralizing antibody against poliovirus in patients with juvenile distal spinal muscular atrophy of upper extremities.

Serum neutralizing antibodies for type 1, 2 and 3 poliovirus were studied in 15 Chinese patients in Taiwan with juvenile distal spinal muscular atrophy of the upper extremities and 15 age-matched normal subjects. Significantly lower serum antibody titers were found in the study group, suggesting that patients with this chronic focal form of acquired motor neuron disease are, to some degree, immunologically unresponsive to the neutralizing epitope of poliovirus.

Adolescent↗