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PubMed1999

[Study of NAIP gene in spinal muscular atrophy].

OBJECTIVE: Investigating the correlation between the genotype and spinal muscular atrophy(SMA) clinical phenotype. METHODS: Neuronal apoptosis inhibitory protein(NAIP) gene analysis was performed by PCR amplification of exon 5 in 13 unrelated SMA patients with deletions of SMN gene. RESULTS: Two Type-I patients(2 M5, 40%) lacked the NAIP exon 5. CONCLUSION: The results suggest a possible correlation between NAIP gene deletion and the disease severity of SMA.

Child↗
PubMed1999

Prenatal diagnosis of spinal muscular atrophy type I (Werdnig- hoffmann) by DNA deletion analysis of cultivated amniocytes.

AIM: Presentation of a prenatally diagnosed case of Werdnig-Hoffmann disease, the most severe type of spinal muscular atrophy. METHODS: DNA obtained from cultivated amniocytes was analyzed for deletions in the survival motor neuron gene and neuronal apoptosis inhibitory protein gene. RESULTS: The fetus was diagnosed as an affected homozygote for deletions in exon 7 and exon 8 of the survival motor neuron gene. No deletions of exon 5 in the neuronal apoptosis inhibitory protein gene were found. CONCLUSION: Direct DNA deletion analysis of the survival motor neuron gene and neuronal apoptosis inhibitory protein gene in affected families represents a highly reliable and fast method for prenatal diagnosis of Werdnig-Hoffmann disease.

Adult↗
PubMed1999

Different molecular basis for spinal muscular atrophy in South African black patients.

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.

Black People↗
PubMed1999

[Utility and intricacy of molecular diagnosis of spinal muscular atrophy].

To diagnose spinal muscular atrophy (SMA), we examined the deletion of exons 7 and 8 of the survival motor neuron (SMN) gene and exon 5 of the neuronal apoptosis inhibitory protein (NAIP) gene in 7 patients from 6 unrelated families, using the polymerase chain reaction method. Two patients with type I and two with type II SMA had the deletion in SMN, whereas 2 of the 3 patients with type III had no deletion in these genes. Thus, the method was not as useful in type III as in type I and II for making a diagnosis of SMA. Together with the data previously reported by others, our data indicated the possibility that the deletion frequency in type III SMA is lower in Japanese patients (< 40%) than in non-Japanese patients (> 80%). Two siblings had SMA of different severity; the older brother having type III and the younger brother type II. Both had the same deletion in the SMN gene. The different phenotypes in these siblings with the same genotype indicated that caution is required when utilizing molecular data for genetic counseling or prenatal diagnosis of SMA.

Child↗
PubMed2000

[Autosomal dominant adult-onset spinal muscular atrophy with vocal cord paralysis: a case report].

This report concerns a 41-year-old female case of spinal muscular atrophy (SMA) associated with vocal cord paralysis. Her parents were not consanguineous. Her maternal grandmother and younger brother were suspected of having SMA. At age 37, she first experienced gait disturbance and began to have slowly progressive dysarthria and weakness of the extremities. Neurological examination revealed that she had inspiratory stridor, dysarthria and proximal muscular weakness of the extremities. Achilles tendon reflexes were absent, while there were no pathological reflexes or sensory disturbances. She showed a waddling gait and Gowers' sign. The laboratory data indicated mild elevation of serum CK. The nerve conduction study was normal, while the electromyographic study and muscle biopsy revealed neurogenic changes. We diagnosed the case as adult onset SMA of the autosomal dominant type. Laryngoscopy revealed that the patient had vocal cord paralysis, which was predominant in abductor muscles and of the posterior paralysis type according to the categories established by Isozaki. Genetic analysis showed no mutations in the genes of the neuronal apoptosis inhibitory protein and of the survival motor neuron.

Adult↗
PubMed2001

Prenatal diagnosis of spinal muscular atrophy in Turkish families.

Prenatal diagnosis of childhood proximal spinal muscular atrophy (SMA) is carried out by the detection of homozygous deletions of survival motor neuron (SMN; exons 7 and 8) and neuronal apoptosis inhibitory protein (NAIP; exons 5 and 6) genes located in 5q13 chromosomal region. In Hacettepe University, Department of Medical Biology, 203 postnatal molecular diagnoses of SMA have been carried out since October 1994 and prenatal diagnosis in subsequent pregnancies to couples who previously had an affected child became possible. Between January 1996 and December 1999 totally 41 SMA families were analyzed by detecting homozygous deletions of SMN and NAIP genes for prenatal counseling. Fetal DNAs were obtained from amniotic fluid and chorionic villus samples. 8/41 (20%) fetal samples were found to be affected and these pregnancies were terminated. It was interesting to find that 2 fetuses had only SMN deletions, however their affected siblings had both SMN and NAIP gene deletions.

Cyclic AMP Response Element-Binding Protein↗
PubMed2001

Correlation between genotype and phenotype in Korean patients with spinal muscular atrophy.

The goal of this study was to define the correlation between genotype and phenotype in Korean patients with spinal muscular atrophy (SMA). The SMA can be classified into three groups based on the age of onset and the clinical course. The candidate genes, survival motor neuron (SMN) gene, neuronal apoptosis inhibitory protein (NAIP) gene, and p44 gene were mapped and duplicated with telomeric and centromeric. The loss of the telomeric SMN occurs by a different mechanism. That is the deletion or conversion of telomeric SMN to centromeric SMN, in which case the conversion could produce a mild phenotype and deletion could produce a severe one. It has been known that there may be a balance between the numbers of copies expressed by the centromeric and telomeric SMN genes. In our study, ten patients with type I SMA and two type II patients were identified by their clinical findings and DNA studies. The major deletion of SMA candidate genes, deletion of the SMN gene, NAIP gene, and p44 gene were identified in six patients with type I SMA, while the rest of type I and all the type II patients showed the deletion of the SMN gene only. Allele numbers of the C212 marker were compared in patients and normal controls in order to find the correlation between the copy numbers and the clinical severity. The result was that type I patients had 2-5 alleles and the normal controls had 4-6. This suggests that the deletion is a major determining factor in the clinical phenotype. However, two type I patients with telomeric NAIP gene deletion notably had 4-5 alleles, as in the normal controls. This result implies that the correlation between the copy numbers and the severity is uncertain as opposed to the previous hypothesis. One type I patient showed the conversion of the centromeric SMN gene to the telomeric, which supports the conclusion that gene conversion is an important molecular mechanism for SMA. In the study of one hundred normal newborns, two physically normal newborns showed deletion of the centromeric SMN gene, suggesting frequent rearrangement in the locus.

Child↗
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↗
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↗