skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

Abstract

Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

Authors:
; ; ; ; ; ; ;  [1];  [2];  [3]
  1. (Hopital des Enfants-Malades, Paris (France))
  2. (Genethon, Evry (France))
  3. (Centre d'Etudes due Polymorphisme Humain, Paris (France))
Publication Date:
OSTI Identifier:
7076039
Resource Type:
Journal Article
Resource Relation:
Journal Name: Science (Washington, D.C.); (United States); Journal Volume: 264:5164
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; HUMAN CHROMOSOME 5; GENETIC MAPPING; MUSCLES; ATROPHY; SPINAL CORD; HEREDITARY DISEASES; GENE MUTATIONS; CENTRAL NERVOUS SYSTEM; CHROMOSOMES; DISEASES; HUMAN CHROMOSOMES; MAPPING; MUTATIONS; NERVOUS SYSTEM; PATHOLOGICAL CHANGES; 550400* - Genetics; 550900 - Pathology

Citation Formats

Melki, J., Lefebvre, S., Burglen, L., Burlet, P., Clermont, O., Reboullet, S., Benichou, B., Zeviani, M., Millasseau, P., and Le Paslier, D. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. United States: N. p., 1994. Web. doi:10.1126/science.7910982.
Melki, J., Lefebvre, S., Burglen, L., Burlet, P., Clermont, O., Reboullet, S., Benichou, B., Zeviani, M., Millasseau, P., & Le Paslier, D. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. United States. doi:10.1126/science.7910982.
Melki, J., Lefebvre, S., Burglen, L., Burlet, P., Clermont, O., Reboullet, S., Benichou, B., Zeviani, M., Millasseau, P., and Le Paslier, D. Fri . "De novo and inherited deletions of the 5q13 region in spinal muscular atrophies". United States. doi:10.1126/science.7910982.
@article{osti_7076039,
title = {De novo and inherited deletions of the 5q13 region in spinal muscular atrophies},
author = {Melki, J. and Lefebvre, S. and Burglen, L. and Burlet, P. and Clermont, O. and Reboullet, S. and Benichou, B. and Zeviani, M. and Millasseau, P. and Le Paslier, D.},
abstractNote = {Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.},
doi = {10.1126/science.7910982},
journal = {Science (Washington, D.C.); (United States)},
number = ,
volume = 264:5164,
place = {United States},
year = {Fri Jun 03 00:00:00 EDT 1994},
month = {Fri Jun 03 00:00:00 EDT 1994}
}
  • Childhood-onset proximal spinal muscular atrophy (SMA) is a heritable neurological disorder, which has been mapped by genetic linkage analysis to chromosome 5q13, in the interval between markers D5S435 and D5S557. Here, we present gene sequences that have been isolated from this interval, several of which show sequence homologies to exons of {beta}-glucuronidase. These gene sequences are repeated several times across the candidate region and are also present on chromosome 5p. The arrangement of these repetitive gene motifs is polymorphic between individuals. The high degree of variability observed may have some influence on the expression of the genes in the region.more » Since SMA is not inherited as a classical autosomal recessive disease, novel genomic rearrangements arising from aberrant recombination events between the complex repeats may be associated with the phenotype observed.« less
  • The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, the authors identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, they have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed. 20 refs., 1 fig.
  • We previously reported that the 400 kb interval flanked the polymorphic loci D5S435 and D5S557 contains blocks of a chromosome 5 specific repeat. This interval also defines the SMA candidate region by genetic analysis of recombinant families. A YAC contig of 2-3 Mb encompassing this area has been constructed and a 5.5 kb conserved fragment, isolated from a YAC end clone within the above interval, was used to obtain cDNAs from both fetal and adult brain libraries. We describe the identification of cDNAs with stretches of high DNA sequence homology to exons of {beta} glucuronidase on human chromosome 7. Themore » cDNAs map both to the candidate region and to an area of 5p using FISH and deletion hybrid analysis. Hybridization to bacteriophage and cosmid clones from the YACs localizes the {beta} glucuronidase related sequences within the 400 kb region of the YAC contig. The cDNAs show a polymorphic pattern on hybridization to genomic BamH1 fragments in the size range of 10-250 kb. Further analysis using YAC fragmentation vectors is being used to determine how these {beta} glucuronidase related cDNAs are distributed within 5q13. Dinucleotide repeats within the region are being investigated to determine linkage disequilibrium with the disease locus.« less
  • Based on a fine genetic and physical map of the region deleted in spinal muscular atrophy, we defined the smallest rearrangements encompassing the SMA gene. This interval is entirely contained in the 903D1 YAC clone. Several approaches to identify candidate genes were applied, including the search for interspecies conservation, exon trapping amplification and direct cDNA selection. Combining these strategies, six different cDNA molecules mapping to the YAC contig were isolated. Four cDNA molecules were isolated using the exon trapping system. They map to chromosome 5p and to more than one locus within the 5q13 region. They are homologous to eachmore » other and share sequence homology with the {beta}-glucuronidase gene. Based on interspecies conservation, a fifth candidate gene was identified. Sequence analyses of the cDNAs revealed no homologies with any other described genes. This gene mapped to two loci within the 5q13 region. Two other cDNA molecules isolated by direct cDNA selection are also under investigation. Complete characterization and fine physical mapping of those genes with respect to the physical interval defined by the deletions of the SMA region will allow the identification of the disease gene (or genes).« less
  • The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both amore » YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array. 39 refs., 5 figs., 2 tabs.« less