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PubMed1993

Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies.

Increased titers of anti-GM1 antibodies have been associated with motor neuron disease and motor neuropathy with or without conduction block. To investigate the pathogenetic role of anti-GM1 antibodies we injected into rat tibial nerves sera from patients with multifocal motor neuropathy and conduction block (MMN) or progressive spinal muscular atrophy (PMA), both presenting anti-GM1 antibodies. Sera of patients with MMN produced reduction of amplitude and dispersion of compound muscle action potential from proximal stimulation. Morphometry revealed demyelination in 6.2% of fibers. Sera of patients with PMA did not produce clear-cut electrophysiological or morphological changes. Differential effects of sera from patients presenting high-titer anti-GM1 antibodies, but with distinct clinical syndromes, might depend on differences in anti-GM1 antibody affinity, valency, or ability to fix complement. Alternatively, circulating factors other than, or in addition to, anti-GM1 antibodies present in sera of patients with MMN, but not of PMA patients, might be responsible for conduction abnormalities and reproduce them after passive transfer.

Animals↗

PubMed2006

Case report: birth after preimplantation genetic diagnosis of a subtle mutation in SMN1 gene.

Spinal muscular atrophy (SMA) preimplantation genetic diagnosis (PGD) has been available since 1998. Protocols are based on the detection of the homozygous deletion of exon 7, which are present in 90-98% of SMA patients. A couple where the woman was a heterozygous carrier of the usual SMN1 Del7 mutation and the man was a heterozygous carrier of pMet263Arg substitution in exon 6 of SMN1 gene was referred for PGD. The usual PGD test being unsuitable for this couple, we developed a novel duplex polymerase chain reaction (PCR)-based PGD test for the detection of the mutation pMet263Arg by allele specific amplification, combined with the amplification of D5S641 extragenic polymorphic marker. PCR conditions were established using single control lymphoblasts and lymphocytes from the pMet263Arg substitution carrier. Amplification was obtained in 100% of the 86 single cells tested, amplification refractory mutation system (ARMS) PCR was specific in 100% of single cells tested and a complete genotype (mutation plus D5S641) was achieved in 88% of them. A PGD cycle was performed successfully and a pregnancy was obtained. An unaffected girl was born and postnatal diagnosis confirmed PGD results. This is the first PGD described for SMA because of another mutation than the major homozygous exon 7 deletion of SMN1. In the future, a similar strategy could be adopted for other subtle mutations of this gene.

Adult↗

PubMed1999

Identification of two distinct transcripts for the neuronal apoptosis inhibitory protein gene.

The spinal muscular atrophies (SMA), characterized by motor neuron loss and progressive paralysis, are among the most common autosomal recessive disorders. Recently, two SMA candidate genes, NAIP (neuronal apoptosis inhibitory protein) and survival motor neuron (SMN), were reported and a 131-kb genomic sequence of 5q13.1 encompassing these two genes was determined. Based upon this genomic sequence, the original NAIP cDNA sequence published in 1995 was shown to contain foreign fragments. We therefore conducted an extensive cDNA cloning of NAIP from a human fetal brain library. Our studies confirmed that the cDNA sequence deduced from the 131-kb genomic sequence was the major transcript in the human fetal brain. In addition, a shorter and minor transcript was also newly identified. We thus designated the longer and shorter transcripts as NAIPl and NAIPs, respectively. The cDNA clones for NAIPl and NAIPs should facilitate the functional analysis of the NAIP gene and its association with neuronal apoptosis and SMA.

Base Sequence↗

PubMed1994

Identification of key recombinants in multiplex SMA families.

Recent reports have provided evidence that a major gene for autosomal recessive proximal spinal muscular atrophy (SMA) resides in a small genetic interval in bands q12-q13 of chromosome 5, a 4-cM region proximally flanked by D5S125 (EF(TG/AG)n) and distally by MAP1B/D5S112 or a 0.7-cM interval (range 0.1-2.1 cM) flanked by D5S435 proximally and MAP1B/D5S112 distally. We present the identification of key recombinants between SMA and the closest flanking DNA-markers in an analysis of Dutch and Italian SMA families. These crossovers may serve as reference points for new markers in this region and may thus be instrumental in a further refined mapping of the SMA gene. Two markers, D5S351 (I105) and D5S357 (Mfd151), could be mapped distally to SMA in the interval SMA-D5S112.

Chromosome Mapping↗

PubMed1999

Comparative sequence analysis of the mouse and human Lgn1/SMA interval.

Human chromosome 5q11.2-q13.3 and its ortholog on mouse chromosome 13 contain candidate genes for an inherited human neurodegenerative disorder called spinal muscular atrophy (SMA) and for an inherited mouse susceptibility to infection with Legionella pneumophila (Lgn1). These homologous genomic regions also have unusual repetitive organizations that create practical difficulties in mapping and raise interesting issues about the evolutionary origin of the repeats. In an attempt to analyze this region in detail, and as a way to identify additional candidate genes for these diseases, we have determined the sequence of 179 kb of the mouse Lgn1/SMA interval. We have analyzed this sequence using BLAST searches and various exon prediction programs to identify potential genes. Since these methods can generate false-positive exon declarations, our alignments of the mouse sequence with available human orthologous sequence allowed us to discriminate rapidly among this collection of potential coding regions by indicating which regions were well conserved and were more likely to represent actual coding sequence. As a result of our analysis, we accurately mapped two additional genes in the SMA interval that can be tested for involvement in the pathogenesis of SMA. While no new Lgn1 candidates emerged, we have identified new genetic markers that exclude Smn as an Lgn1 candidate. In addition to providing important resources for studying SMA and Lgn1, our data provide further evidence of the value of sequencing the mouse genome as a means to help with the annotation of the human genomic sequence and vice versa.

Animals↗

PubMed2000

Evolutionary divergence of the mouse and human Lgn1/SMA repeat structures.

The orthologous genomic segments on mouse chromosome 13D1-D3 and human chromosome 5q11.2-q13.3 have been extensively studied because of their involvement in two distinct disease phenotypes, spinal muscular atrophy (SMA) in human and susceptibility to Legionella pneumophila (determined by Lgn1) in mice. The overlapping intervals in both species contain genomic amplifications of distinct structure, indicating an independent origin. We have endeavored to construct a comprehensive comparative gene map of the mouse and human Lgn1/SMA intervals in the hopes that the origins and maintenance of the genomic amplifications may become clear. Our comparative gene map demonstrates that the only regional gene in common between the amplified segments in mouse and human is the Lgn1 candidate Naip/NAIP. We have also determined that mice of the 129 haplotype harbor seven intact and three partial Naip transcription units arranged in a closely linked direct repeat on chromosome 13. Several, but not all, of these Naip loci are contained within the Lgn1 critical interval. We present a model for the origins of the mouse and human repetitive arrays from a common ancestral haplotype.

5' Untranslated Regions↗

PubMed1995

Mapping of a human rRNA gene in the YAC contig surrounding the SMA candidate gene.

Using the yeast artificial chromosome (YAC) 116 flanking the autosomal recessive spinal muscular atrophy (SMA) gene region, we have screened a human fetal brain cDNA library and isolated the cDNA clone 14-3/9 with an insert size of 2.5 kb. The cDNA clone could be identified as part of the human rRNA gene coding for 28S rRNA with a total size of 5025 bp. The human 28S rRNA is involved in the organization of the 60S ribosomal subparticle and is arranged in a 13-kb pre-rRNA transcription unit that occurs in tandem repeat clusters. Multiple copies of the rRNA gene have been mapped by pulsed field blot hybridization in the YAC contig between YAC 66 and YAC 116, which encompasses the SMA candidate gene, and additionally in the distally localized YAC 153.

Adult↗

PubMed1995

Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration.

Neuromuscular degeneration, nmd, is a spontaneous autosomal recessive mutation in the mouse producing progressive hindlimb impairment caused by spinal muscular atrophy. We used an intersubspecific intercross between B6.BKs-nmd2J/+ and Mus musculus castaneus (CAST/Ei) to map the nmd mutation to mouse Chromosome (Chr) 19 with the most likely gene order: nmd-(D19Sel2, Pygm)-Cntf-Pomc2-D19Mit16-Cyp2c-Got1. nmd maps near muscle deficient, mdf, and has a very similar clinical phenotype, but allele tests and histological differences suggest that nmd is a distinct mutation at a different locus. Although closely linked, nmd recombined with the candidate genes muscle glycogen phosphorylase, Pygm, and ciliary neurotrophic factor, Cntf.

Animals↗

PubMed1988

A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya.

A 4-year-search for spinal muscular atrophies (hereditary motor neuropathies, HMN) in Benghazi, Libya, yielded a total of 24 patients, among whom 18 were index cases. This group comprised 6 acute infantile, 12 chronic childhood, and 3 each with adult-onset proximal, and distal forms of the disorder. Distal HMN constituted 12.5% of the total cases. The crude average annual incidence of acute infantile HMN was 0.3/100,000 total population and 1/12,500 births in Benghazi. The crude prevalence rates of chronic childhood, adult-onset proximal, and distal types of HMN were 2.3, 0.6, and 0.6/100,000 respectively. The segregation ratios, 0.26 for acute infantile HMN and 0.24 for chronic childhood HMN, suggested autosomal recessive inheritance. The consanguinity rates among parents of cases and the population did not differ significantly.

Acute Disease↗

PubMed1977

Inbreeding in recessive diseases.

The consanguinity of parents (born in France) of individuals who have a recessive disease has been studied. The frequency of first cousin marriages is less than 0.2% in the general French population. Among the parents of affected individuals the following frequencies of first cousin matings were observed: cystic fibrosis: 1.4% cystinosis: 7.1% nephronophtisis: 5.6% spinal muscular atrophy: 4.5% albinism: 5.0% achromatopsia: 12.5% (Albinism and spinal muscular atrophy are heterogeneous conditions). The increase in the frequency of first cousin marriage relative to that of the general population is much greater, as expected, in cystinosis, which is a rare disease, than in cystic fibrosis, which is the most frequent recessive disorder in France. Inbreeding in cystinosis and cystic fibrosis was also studied by computing the distance between parental birth places. This distance is smaller in cystinosis than in cystic fibrosis.

Albinism↗

PubMed1995

Urinary excretion of lead and mercury after oral administration of meso-2,3-dimercaptosuccinic acid in patients with motor neurone disease.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive neurodegenerative disorders involving motor neurones. The aetiology of the non-familiar forms is still unknown but it has been suggested that long-term exposure to heavy metals such as lead and mercury may play a role in the pathogenesis of these diseases. In 53 patients suffering from ALS (n = 42) and SMA (n = 9) the oral administration of dimercaptosuccinic acid (DMSA, 20 mg/kg) did not result in a greater mobilization of lead and mercury from peripheral depots than in control subjects. Although it cannot be excluded that the amount of lead or mercury excreted after DMSA administration may not be a reflection of the amount accumulated in the motor neurons, this study does not provide support for the hypothesis that heavy metals play a significant role in the occurrence of motor neurone diseases.

Adult↗

PubMed1996

Non-invasive early prenatal molecular diagnosis using retrieved transcervical trophoblast cells.

Fetal DNA was recovered from 17 of 39 (44%) transcervical cell (TCC) samples obtained between 7 and 9 weeks of gestation by endocervical canal flushing. Trophoblast retrieval was adequate for polymerase chain reaction (PCR) amplification of Y chromosome-specific DNA sequences and detection of paternal-specific microsatellite alleles. The fetal sex predicted by PCR in TCCs was confirmed in all cases by karyotype analysis of chorionic villi at 10 weeks of gestation. The absence of the disease-associated paternal alleles in TCC samples from two pregnancies at risk for spinal muscular atrophy and myotonic dystrophy predicted unaffected fetuses in agreement with subsequent results on chorionic villi and newborns' leukocytes. A trisomy 21 fetus was diagnosed in TCCs using fluorescent in situ hybridization (FISH) and semi-quantitative PCR analysis of superoxide dismutase-1 (SOD 1). Present experience indicates that TCC sampling is a promising technique for early prenatal monitoring of Mendelian disorders and chromosome aneuploidy.

Adult↗

PubMed2002

Genetic study of SMA patients without homozygous SMN1 deletions: identification of compound heterozygotes and characterisation of novel intragenic SMN1 mutations.

Autosomal recessive spinal muscular atrophy (SMA) is a disease resulting from mutations in the telomeric survival motor neuron gene ( SMN1). In our sample of 150 Spanish SMA families, 87% of patients had homozygous deletions of SMN1. To identify patients who retained a single SMN1 copy, SMN dosage analysis was performed by a fluorescent quantitative PCR assay. In five out of 19 patients tested we detected one SMN1 copy. An extensive SMN gene analysis in these patients led to identification of four intragenic mutations, including two novel ones: a frameshift mutation in exon 6 (773insC) and a splice site mutation in intron 6 (c.867+2T-->G). Two previously described mutations were also found: a deletion in exon 3 (430del4), identified in several Spanish patients, and a frequently occurring mutation in exon 6 (813ins/dup11), reported in several populations. Although the spectrum of intragenic mutations is small, only 27 reported up to now, identification of three mutations found exclusively in the Spanish population indicates that the occurrence of different intragenic mutations depends on the ethnic origin of SMA patients. In the remaining patient, who had a single SMN1 copy and three SMN2 copies, we found that the SMN1 allele was non-functional; the patient did not show any SMN1 transcript. Sequencing of the SMN promoter regions revealed various differences between promoters of the patient's four SMN genes, in particular a change in the length of a polyA run removing a putative YY1 binding site, which may affect the expression of SMN genes.

Alleles↗

PubMed2003

Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.

Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutations of the SMN1 gene. SMN1 interacts with multiple proteins with functions in snRNP biogenesis, pre-mRNA splicing and presumably neural transport. SMN2, a nearly identical copy of SMN1, produces predominantly exon 7-skipped transcripts, whereas SMN1 mainly produces full-length transcripts. The SR-like splicing factor Htra2-beta1 facilitates correct splicing of SMN2 exon 7 through direct interaction with an exonic splicing enhancer within exon 7. In rare cases, siblings with identical 5q13-homologues and homozygous absence of SMN1 show variable phenotypes, suggesting that SMA is modified by other factors. By analysing nine SMA discordant families, we demonstrate that in all families unaffected siblings produce significantly higher amounts of SMN, Gemin2, Gemin3, ZPR1 and hnRNP-Q protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected siblings. Protein p53, an additional SMN-interacting protein, is not subject to an SMN-dependent regulation. Surprisingly, Htra2-beta1 is also regulated by this tissue-specific mechanism. A similar regulation was found in all type I-III SMA patients, although at a different protein level than in discordant families. Thus, our data show that reduced SMN protein levels cause a reduction in the amount of its interacting proteins and of Htra2-beta1 in both discordant and non-discordant SMA families. We provide evidence that an intrinsic SMA modifying factor acts directly on the expression of SMN, thus influencing the SMA phenotype. Further insights into the molecular pathway and the identification of SMA modifying gene(s) may help to find additional targets for a therapy approach.

Adult↗

PubMed2001

Characterisation of SMN hybrid genes in Spanish SMA patients: de novo, homozygous and compound heterozygous cases.

Autosomal recessive spinal muscular atrophy (SMA) is classified, by age of onset and maximal motor milestones achieved, into type I (severe form), type II (intermediate form) and type III (mild/moderate form). SMA is caused by mutations in the survival motor neuron telomeric gene (SMN1) and a centromeric functional copy of this gene (SMN2) exists, both genes being located at 5q13. Homozygous deletion of exons 7 and 8 of SMN1 has been detected in approx 85% of Spanish SMA patients regardless of their phenotype. Nineteen cases with the sole deletion of exon 7 but not exon 8 (2 cases of type I, 13 cases of type II, four cases of type III) were further analysed for the presence of SMN2-SMN1 hybrid genes. We detected four different hybrid structures. Most of the patients were carriers of a hybrid structure: centromeric intron 6- centromeric exon 7- telomeric exon 8 (CCT), with or without neuronal apoptosis-inhibitor protein (NAIP). In two patients, a different hybrid structure, viz. telomeric intron 6- centromeric exon 7- telomeric exon 8 (TCT), was detected with or without NAIP. A phenotype-genotype correlation comparing the different structures of the hybrid alleles was delineated. Type I cases in our series are attributable to intrachromosomal deletion with a smaller number of SMN2 copies. Most cases with hybrid genes are type II occurring by a combination of a classical deletion in one chromosome and a hybrid gene in the other. Type III cases are closely associated with homozygozity or compound heterozygozity for hybrid genes resulting from two conversion events and have more copies of hybrid genes and SMN2 than type I or II cases.

Alleles↗

PubMed1996

Frequent DNA variant in exon 2a of the survival motor neuron gene (SMN): a further possibility for distinguishing the two copies of the gene.

An intragenic single-strand conformation polymorphism (SSCP) variant in exon 2a of the survival motor neuron gene (SMN) has been identified. The SSCP band shift is caused by a silent mutation (AGC-->AGT) at codon 28, which is the first codon of exon 2a. Five exchanges of base pairs at the 3'-end of the gene have been described that allow the two copies of SMN (telSMN and cenSMN) to be distinguished, whereas no DNA variant has been found at the 5'-end. The new DNA variant belongs to cenSMN and may be important for the assignment of point mutations to one of the two copies of SMN in spinal muscular atrophy (SMA) patients. The frequency of this variant is lower in SMA patients (10%) than in controls (24%).

Base Sequence↗

PubMed2001

Characterisation of novel point mutations in the survival motor neuron gene SMN, in three patients with SMA.

We report two novel mutations in three cases of spinal muscular atrophy (SMA), including two distant cousins who followed an unexpectedly severe course. Diagnosis was confirmed by reduced SMN protein and full-length SMN mRNA levels. Sequencing of the non-deleted SMN1 gene revealed a single G insertion at the end of exon 1 in the two cousins and a novel G275S exon 6 missense mutation in the milder case.

Child↗

PubMed2000

The survival motor neuron (SMN) protein: effect of exon loss and mutation on protein localization.

Spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of the survival motor neuron gene (SMN1) but not mutations in the centromeric copy (SMN2). The critical difference between the two genes is a nucleotide difference in exon 7 that affects splicing and causes this exon to be spliced out of most SMN2 transcripts. A majority of the SMN1 gene transcripts contain exon 7. To investigate the effect of exon loss or mutations in SMN on protein localization, 15 SMN constructs were prepared and transfected into COS-7 cells and fibroblasts derived from a type I SMA patient. Loss of exon 5 (Iso5-SMN), a putative nuclear localization signal in exon 2, and the G279V point mutation had little effect on SMN localization. Loss of both exons 5 and 7 (Iso57-SMN) resulted in low gem numbers and the localization of the majority of the SMN protein to the cytoplasm. Cells expressing constructs lacking only exon 7 (Iso7-SMN) did not produce large numbers of gems in general, although there were a few cells that had a staining pattern similar to cells transfected with a full-length (Full-SMN) construct. HeLa cells stably transfected with full-length SMN or Iso7-SMN did not overexpress SMN, and both constructs produced a similar localization of the protein, although Iso7-SMN formed gems less efficiently. Removal of the amino-terminus, deletion of the conserved domain in exon 2A, and the mutation Y272C all caused accumulation of SMN in the nucleus, sometimes in large aggregates. These findings suggest that the amino-terminal domain of SMN is essential for the correct cellular distribution of SMN, whereas Iso7-SMN is capable of forming gems, albeit at a reduced efficiency.

Animals↗