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PubMedDate not supplied

[Spinal muscular atrophy: SMN protein deficiency].

Spinal muscular atrophy is a heterogeneous group of disorders characterised by the loss of alfa motor neurons in spinal cord. Autosomal recessive infantile and juvenile proximal spinal muscular atrophy is the most common form of the disease. The identification of the disease gene-Survival of Motor Neuron (SMN) was a major advance in understanding of the molecular basis of SMA. 98% of SMA patients show the homozygous absence of at least exon 7 telomeric copy of SMN, the rest carry small intragenic mutations, usually in exon 6. Two different mechanisms seem to be responsible for the absence of the telomeric copy: deletion in severe form and gene conversion associated with mild phenotype. Recently, biochemical studies resulted in identification of the 38kDa survival motor neuron (SMN) protein, probably involved in the biogenesis of spliceosomal snRNP. The SMN protein level was shown to be 100-fold reduced in spinal cord of SMA 1 patients.

Cyclic AMP Response Element-Binding Protein↗
PubMed2001

[A study of survival motor neuron and neuronal apoptosis inhibitory protein gene in spinal muscular atrophy].

OBJECTIVE: To study the absence of survival motor neuron(SMN) gene exon 7,8 and neuronal apoptosis inhibitory protein(NAIP) gene exon 5,6 in Chinese patients with type I - IV spinal muscular atrophy (SMA) and to confirm the relationship between the deletions of SMN, NAIP and SMA phenotype. METHODS: PCR and PCR-enzyme methods were used to detect the deletions of NAIP gene exon 5,6 and SMN gene exon 7,8 in 45 SMA (I - IV) patients and 30 healthy relatives of the patients and 30 normal controls. RESULTS: Deletions of exon 7 and 8 of the telomeric SMN gene were 4/4, 2/3, 1/8 and 0/30 in type I, II, III and IV SMA patients, respectively. One patient with type II lacked the exon 7 but retained exon 8. No deletions was found in the relatives and controls(0/60). No deletions of exon 5 and 6 of the NAIP gene was detected in all the patients, healthy relatives and controls. CONCLUSIONS: Deletions of SMN gene exon 7 and 8 exa mined by PCR-enzyme digestion could be recommended as an accurate gene diagnostic method for SMA with type I and II. However, the method was not as useful in type III as in I and II for making a diagnosis of SMA. Type IV SMA, a heterogeneous disease with phenotypical similarities to type I - III SMA, may be caused by deletion of other genes. The frequency of NAIP deletion was lower in Chinese SMA patients.

Child↗
PubMed2002

The loss of IAP expression during HL-60 cell differentiation is caspase-independent.

Human promyelocytic leukaemia cells (HL-60) differentiate into neutrophil-like cells that die spontaneously by apoptosis when treated with retinoic acid (RA). Inhibitors of apoptosis proteins (IAP) bind to and inhibit caspases 3, 7, and 9 activity and the induction of apoptosis. In this study, we demonstrate that undifferentiated HL-60 cells express IAP. During their differentiation, IAP expression is decreased at the mRNA and protein levels. In addition, we show that there is a corresponding increase in the expression and functional activity of active caspases 3 and 9. This activity was associated with the cleavage of XIAP, NAIP, and cIAP-2. Most importantly, we demonstrate that blocking caspase activity does not alter the decrease in IAP protein expression during differentiation but prevents caspase activation, IAP cleavage, and the induction of apoptosis. This result shows that the loss of IAP expression is independent of the induction of apoptosis and is solely related to the differentiation process. However, IAP cleavage is caspase-dependent. Terminal differentiation results in an altered apoptotic phenotype that is associated with the induction of HL-60 cell apoptosis.

Apoptosis↗
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↗
PubMed2001

Phenotype and genotype correlation in childhood spinal muscular atrophy.

In the period 1998-2000 almost all new cases of childhood spinal muscular atrophy (SMA) in addition to those from our database were studied for possible deletion of SMN gene (exons 7 a 8) and NAIP (exons 5 a 6). We correlated the size of deletion with the type, course and the onset of disease. The most informative for diagnosis was deletion of SMN. NAIP was deleted only in 18% of all cases, usually in SMA1 (in only 2 cases of SMA2). The molecular genetics permits to come back to previously posed question about the extremely frequent intrafamilial variability in SMA families. The problem became more clear due to our knowledge on telomeric and centromeric copies, as well as various genes and paragenes involved in SMA region. In the premolecular era we postulated the gender influence on course of the disease, which is particularly evident in mild SMA form 3b. Interestingly, presently we and some others detected deletion similar to those in the patients among the clinically healthy siblings. Those siblings are mostly females. The other problem, byproduct of molecular genetic, is the occurrence of SMN deletion in some disorders till now considered entirely different from SMA, e.g., arthrogryposis, congenital hypomyelinating neuropathies of newborn.

Child↗
PubMed2000

[Survival motor neuron gene and neuronal apoptosis inhibitory protein gene deletion in patients with spinal muscular atrophy].

OBJECTIVE: To investigate the frequencies of gene deletion survival motor neuron telomere (SMNTel) exon 7 and neuronal apoptosis inhibitory protein gene (NAIP) exon 5 in 55 Chinese spinal muscular atrophy (SMA) patients, and compare the relationship between these two candidate genes and the disease. METHODS: PCR-SSCP method was used to detect the deletion of SMNTel exon 7, direct visualization of PCR products by agarose electrophoresis was used to detect the deletion of NAIP exon 5 in 55 SMA patients with type I and type II. 40 normal individuals were involved in the study as controls. RESULTS: Homozygous deletion of the SMNTel exon 7 was identified in 92% (23/25) of SMA type I patients and 90% (27/30) of SMA type II patients. The same deletion was found in two mothers and one father of SMA patients. There was no homozygous deletion found in normal controls. None of the homozygous deletion of NAIP exon 5 was found in 55 SMA patients and normal controls. Only two patients were found to have the heterozygous deletion. CONCLUSIONS: The frequency of homozygous deletion of SMNTel exon 7 was 90.1%. Our data support that SMN gene is strongly associated with SMA.

Adult↗
PubMed1995

Programmed cell death and the gene behind spinal muscular atrophy.

A gene involved in the development of spinal muscular atrophy (SMA) has been found on human chromosome 5 after a 4-year search. Named the neuronal apoptosis inhibitor protein (NAIP) gene, it is believed to inhibit the normal process of apoptosis--the disintegration of single cells that results from programmed cell death--in motor neurons. The researchers who found the NAIP gene also discovered that healthy people carry one complete copy of the gene along with many other partial copies. Many children with SMA have the partial copies but not the complete gene. This discovery facilitates the accurate genetic diagnosis of SMA. But gene therapy for SMA will not be possible until researchers find a suitable vector to stably introduce activated and intact copies of the gene into the motor neurons of children with SMA in time to stop motor neuron loss.

Apoptosis↗
PubMed1996

[The contribution of molecular genetics to the study of spinal muscular atrophy].

Spinal muscular atrophies constitute a group of hereditary diseases characterized by degeneration of the anterior horn of the spinal cord. Molecular studies began in 1990 with the location of the genome region responsible for the disease in chromosome 5q13. New directions for research were opened in 1995 with the identification of the affected region in the survival motor neuron (SMN) genes and the neuronal apoptosis inhibitory protein genes. A main feature of these genes is that they are duplicate, forming part of two elements (centromeric and telomeric) that include mini-satellites that are also repeated, making this zone particularly unstable. The molecular abnormalities found in patients are a consequence of that instability: gene deletions and conversions in the SMN gene have been described independently of whether symptoms were severe or not. Molecular data make it possible to confirm the clinical diagnosis of most patients and to provide certain prenatal diagnosis for couples that are at high risk of passing on the disorder. Determining both the function of these genes and their pathogenesic role will help to ground new therapeutic strategies that will prevent or detain motor neuron degeneration.

Apoptosis↗
PubMed1997

Clinical application of the molecular diagnosis of spinal muscular atrophy: deletions of neuronal apoptosis inhibitor protein and survival motor neuron genes.

The molecular genetic diagnosis of spinal muscular atrophy (SMA) has recently been complicated by the identification of two candidate genes, which are often deleted in affected individuals but are also occasionally deleted in apparently unaffected carriers. We present a compilation of genotypes, from our laboratory and recent reports, for the survival motor neuron (SMN) and neuronal apoptosis inhibitor protein (NAIP) genes. Bayesian analyses were used to generate probabilities for SMA when deletions are present or absent in SMN. We found that when the SMN(T) exon 7 is deleted, the probability of SMA can reach greater than 98% in some populations, and when SMN(T) is present, the probability of SMA is approximately 17 times less than the prior population risk. Deletion of NAIP exon 5, as well as SMN(T) exon 7, is associated with a 5-fold increased risk of type I SMA. Case studies are used to illustrate differing disease risks for pre- and postnatal testing, depending on the presence of information about clinical status or molecular results. These analyses demonstrate that deletion screening of candidate genes can be a powerful tool in the diagnosis of SMA.

Cyclic AMP Response Element-Binding Protein↗
PubMed1997

Distribution of neuronal apoptosis inhibitory protein-like immunoreactivity in the rat central nervous system.

We have recently shown that spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by motor neuron loss, is associated with deletion of a gene that encodes the neuronal apoptosis inhibitory protein (NAIP). In the present study, we have examined the distribution of NAIP-like immunoreactivity (NAIP-LI) in the rat central nervous system (CNS) by using an affinity-purified polyclonal antibody against NAIP. In the forebrain, immunoreactive neurons were detected in the cortex, the hippocampus (pyramidal cells, dentate granule cells, and interneurons), the striatum (cholinergic interneurons), the basal forebrain (ventral pallidum, medial septal nucleus, and diagonal band), the thalamus (lateral and ventral nuclei), the habenula, the globus pallidus, and the entopenduncular nucleus. In the midbrain, NAIP-LI was located primarily within neurons of the red nucleus, the substantia nigra pars compacta, the oculomotor nucleus, and the trochlear nucleus. In the brainstem, neurons containing NAIP-LI were observed in cranial nerve nuclei (trigeminal, facial, vestibular, cochlear, vagus, and hypoglossal nerves) and in relay nuclei (pontine, olivary, lateral reticular, cuneate, gracile nucleus, and locus coeruleus). In the cerebellum, NAIP-LI was found within both Purkinje and nuclear cells (interposed and lateral nuclei). Finally, within the spinal cord, NAIP-LI was detected in Clarke's column and in motor neurons. Taken together, these results indicate that NAIP-LI is distributed broadly in the CNS. However, high levels of NAIP-LI were restricted to those neuronal populations that have been reported to degenerate in SMA. This anatomical correspondence provides additional evidence for NAIP involvement in the neurodegeneration observed in acute SMA.

Animals↗
PubMed1998

[Detection of SMN gene deletions in spinal muscular atrophy].

OBJECTIVE: Survival motor neuron gene(SMN) and neuronal apoptosis inhibitory protein gene (NAIP) have been identified as the candidates of progressive spinal muscular atrophy (SMA)-determining genes. The aims of this study were to investigate the absence of SMN gene exon 7 in Chinese SMA patients, to confirm the relationship between the deletion of the SMN and SMA further, and to establish methods for gene diagnosis and prenatal diagnosis of SMA. METHODS: PCR-SSCP with silver staining method was used to detect the genomic DNA of 37 SMA patients and 30 normal individuals for deletions of SMN exon 7. RESULTS: Homozygous deletion of the SMN exon 7 was identified in 86.7%(13/15) of type I SMA patients and 86.4%(19/22) of type II patients. In the 88 controls (including parents of patients and normal individuals), homozygous absence of SMA exon 7 was only found in a mother of a patient. CONCLUSION: The data support that homozygous absence of SMN exon 7 is strongly associated with SMA. The percentage of homozygous deletions in this study is almost as high as that reported by other researchers. This method is useful, reliable and effective for gene diagnosis and prenatal diagnosis of SMA.

Cyclic AMP Response Element-Binding Protein↗
PubMed1999

Spinal muscular atrophy: untangling the knot?

Spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of neuromuscular diseases, is a disorder of motor neurones characterised by degeneration of spinal cord anterior horn cells and muscular atrophy. SMA is an autosomal recessive disorder with a carrier frequency of about 1150. Three candidate genes, the survival motor neurone (SMN) gene, the neuronal inhibitory protein (NAIP) gene, and the p44 (subunit of basal transcription factor TFIIH) gene, have been considered as genes involved in this condition. The region spanning these genes has a complex organisation including duplications, repetitive sequences, truncated genes, and pseudogenes, which makes molecular analysis of this condition difficult. Although deletions have been found in the majority of SMA patients, a few microrearrangements (like duplications, missense mutations, microdeletions, and gene conversions) localised in the telomeric form of the SMN gene have also been reported. The function of the protein encoded by the SMN gene is still not fully understood but recent studies have indicated that it is found intracellularly in gems, novel nuclear structures. Its interaction with other proteins suggests a role in mRNA processing and metabolism. Whether the NAIP gene protein and other apoptosis associated proteins are directly involved in the initial stages of neurone degeneration and apoptosis, or acting downstream on the pathological pathway, has been difficult to determine. Further studies will be required to elucidate possible functional interactions between these proteins.

Autoantigens↗
PubMed2001

NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-OHDA rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.

Amphetamine↗
PubMed1999

[Apoptotic cell death in child-onset neurodegenerative disorders].

Apoptotic cell death was examined in autopsied brains with Werdnig Hoffmann disease, hereditary DNA repair disorders (xeroderma pigmentosum and Cockayne syndrome) and neuronal ceroid lipofuscinosis, using in situ nick end labeling (TUNEL) and immunohistochemistry for cell death-related proteins. TUNEL-positive cells were found in the thalamus, cerebellum and/or hippocampus in each disorder. The expression of cell death-related proteins in the cerebellum of hereditary DNA repair disorders and the hippocampus of neuronal ceroid-lipofuscinosis suggested the involvement of apoptotic process in neurodegeneration in these disorders. On the other hand, TUNEL-reactivity without the altered expression of cell death-related proteins might reflect neuronal changes preceding the thalamic degeneration in Werdnig-Hoffmann disease.

Adolescent↗
PubMed1996

The mouse region syntenic for human spinal muscular atrophy lies within the Lgn1 critical interval and contains multiple copies of Naip exon 5.

Spinal muscular atrophy (SMA) is a relatively common, autosomal recessively inherited neurodegenerative disorder that maps to human chromosome 5q13. This region of the human genome has an intricate genomic structure that has complicated the evaluation of SMA candidate genes. We have chosen to study the mouse region syntenic for human SMA in the hope that the homologous mouse interval would contain the same genes as human 5q13 on a simpler genomic background. Here, we report the mapping of such a region to mouse chromosome 13 and to the critical interval for Lgn1, a mouse locus responsible for modulating the intracellular replication and pathogenicity of the bacterium Legionella pneumophila. We have generated a mouse YAC contig across the Lgn1/Sma interval and have mapped the two flanking gene markers for the human SMA locus, MAP1B and CCNB1, onto this contig. In addition, we have localized the two SMA candidate genes, SMN and NAIP, to the Lgn1 critical region, making these two genes candidates for the Lgn1 phenotype. Upon subcloning of the YAC contig into P1s and BACs, we have detected a large, low copy number repeat that contains at least one copy of Naip exon 5. Identification of the Lgn1 gene will either provide a novel function for SMN or NAIP or reveal the existence of another, yet uncharacterized gene in the SMA critical region. Mutations in such a gene might help to explain some of the phenotypic variability among the human SMAs.

Animals↗