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PubMed1996

Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease.

Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann disease), type II (intermediate form), and type III (Kugelberg-Welander disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman disease (type I) and allows one to predict the severity of the disease in our series.

Adult↗
PubMed1996

FISH detection of chromosome polymorphism and deletions in the spinal muscular atrophy (SMA) region of 5q13.

The search for the SMA defect has culminated in the identification of two candidate 5q13.1 SMA genes, NAIP and SMN both of which are deleted in individuals with SMA. It was postulated that the intact and degenerate versions of NAIP are present in variable and frequently high copy numbers in this region while SMN was proposed to be present in only two copies. In order to assess the copy number of NAIP and SMN we have conducted interphase FISH analysis using NAIP and SMN gene-containing cosmid and plasmid probes. Our results confirm the variability in the number of NAIP signals in non-SMA chromosomes (2-6) and show that SMN is present on average twice per chromosome although in one chromosome 4-5 signals for the SMN-containing cosmid probe were detected. Our analysis reveals that one of four and three of six type I SMA chromosomes had a lower than normal number of NAIP and SMN signals, respectively. In two of six SMA type I chromosomes, complete loss of hybridization signal was observed on one chromosome 5 with our SMN cosmid probe possibly reflecting a large scale deletion. Large scale deletions were not detectable when metaphase chromosomes of an SMA type II and III patient were analyzed.

Chromosome Deletion↗
PubMed1995

A provisional transcript map of the spinal muscular atrophy (SMA) critical region.

YACs from the region containing the spinal muscular atrophy (SMA) locus at 5q12 have been used as probes in a direct screening of cDNA libraries to isolate 8 cDNAs, mapped to different YAC fragments. Three clones showed complete identity to the genes for cyclin B1 (CCNB1), the p44 subunit of the transcription factor BTF2 (BTF2p44), and cofilin (CFL). Two clones showed partial identity to the beta-glucuronidase gene (GLCB) and a rat integral membrane glycoprotein gene (RNINMEGLA). CFL turned out to have been identified by a pseudogene sequence. Related sequences occurred on other chromosomes. CCNB1 and BTF2p44 were given an exact location. The GLCB-like gene and the RNINMEGLA-like gene detected loci on both 5q and 5p. The remaining three cDNA clones were localized to the SMA region only. Their sequences did not show identity to any gene for which a function is already known. Two of them have now turned out to be identical to recently reported candidate genes for SMA.

Actin Depolymerizing Factors↗
PubMed1998

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy.

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.

Adult↗
PubMed1998

Large-scale deletions in a Chinese infant associated with a variant form of Werdnig-Hoffmann disease.

A Chinese male infant with arthrogryposis multiplex congenita (AMC), ventricular and atrial septal defects, and Werdnig-Hoffmann disease (WHD) had deletions of the telomeric copy of the survival motor neuron (SMN(T)) and neuronal apoptosis inhibitory protein genes. Children with AMC or congenital heart disease, or both, and motor neuron disease should undergo testing for SMN(T) deletion. This rare association further illustrates the variable phenotypic expressions of WHD.

Arthrogryposis↗
PubMed1998

Expression and regulation of neuronal apoptosis inhibitory protein during adipocyte differentiation.

We have used the 3T3-L1 and 3T3-F442A preadipocyte cell lines to examine the expression and regulation of neuronal apoptosis inhibitory protein (NAIP) during adipocyte differentiation. When 3T3-L1 preadipocytes differentiated into adipocytes, they developed resistance to apoptosis induced by growth factor deprivation, as assessed by terminal deoxynucleotide transferase (TdT)-mediated dUTP nick end labeling. Protein expression of NAIP was markedly elevated in 3T3-L1 and 3T3-F442A adipocytes compared with that in their fibroblast-like precursors. NAIP was also present in rat white adipocytes. In 3T3-L1 cells, the increase in NAIP occurred by day 4 of the 8-day differentiation protocol, which includes exposure of confluent preadipocytes to insulin, dexamethasone, and isobutylmethylxanthine. Incubation of confluent 3T3-L1 preadipocytes with any of these components alone had no effect on NAIP expression. When 3T3-C2 cells, a control cell line that does not differentiate, were subjected to the differentiation protocol, the low NAIP levels remained unaltered. Addition of rapamycin, a p70 S6 kinase inhibitor that blocks adipocyte differentiation, to the 3T3-L1 differentiation medium prevented the rise in NAIP expression. These data demonstrate for the first time that NAIP is expressed in adipocyte cell lines and primary adipocytes. The differentiation-dependent augmentation of NAIP protein levels in 3T3-L1 adipocytes is closely correlated with the development of resistance to apoptosis induced by growth factor deprivation, suggesting a potential role for NAIP in these cells.

3T3 Cells↗
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↗
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↗