Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): Confirmation of close linkage to D5S39 in French Canadian families

doi:10.1016/S0888-7543(05)80305-2

Genomics

Volume 14, Issue 1, September 1992, Pages 188-190

https://doi.org/10.1016/S0888-7543(05)80305-2 Get rights and content

Chronic childhood-onset spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. Recent linkage analyses have mapped this disease to 5q12–5q14. We show that chronic SMA (Types II and III) is tightly linked to the marker locus D5S39 (Z_max = 5.47 at ϑ = 0.02) in eight French Canadian families. In contrast to previously published results, we do not observe close linkage between chronic SMA and D5S6 (Z_max = 0.34 at ϑ = 0.18) or D5S78 (Z_max = 0.25 at ϑ = 0.21). Last, we present a family that appears to be discordant for this localization but may represent the first example of an incompletely penetrant individual.

References (18)

DanielsR.J. et al.
Linkage analysis of spinal muscular atrophy
Genomics
(1992)
MelkiJ. et al.
Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12–q14
Lancet
(1990)
PearnJ.
Classification of spinal muscular atrophies
Lancet
(1980)
AbdelhakS. et al.
A PstI polymorphism at the D5S39 locus
Nucleic Acids Res.
(1990)
BishopD.T. et al.
Report of the committee on the genetic constitution of chromosome 5
Cytogenet. Cell Genet.
(1990)
BrzustowiczL.M. et al.
Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3
Nature
(1990)
ConneallyP.M. et al.
Report of the committee on methods of linkage analysis and reporting
Cytogenet. Cell Genet.
(1985)
DubowitzD.
Muscle Disorders in Childhood
GilliamT.C. et al.
Genetic homogeneity between acute and chronic forms of spinal muscular atrophy
Nature
(1990)

There are more references available in the full text version of this article.

Cited by (24)

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2
2002, Genetics in Medicine
Purpose: This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing.
Methods: From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients.
Results: Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients.
Conclusions: SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing. Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information.
The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy
2001, Brain and Development
Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder with progressive weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is present in two highly homologous copies (SMN1 and SMN2) on chromosome 5q13. Homozygous deletion of exons 7 and 8 of SMN1 is responsible for spinal muscular atrophy. In spinal muscular atrophy patients, SMN2 partially compensates for the lack of SMN1. Previously, we reported the relatively high incidence of a large deletion including the SMN1 region in Japanese spinal muscular atrophy type I patients. In order to further establish the genetic background of Japanese spinal muscular atrophy type I patients, we investigated the SMN1/SMN2 ratio in the carriers. In normal individuals, there is one copy of each gene on the chromosome (the SMN1/SMN2 ratio was 1). Among 15 carriers (14 parents and one carrier sibling of Japanese type I spinal muscular atrophy patients with homozygous deletion of exons 7 and 8 of SMN1), we found that the SMN1/SMN2 ratio was 0.5 or 1 in 11 (73.3%) carriers. The remaining four carriers had an SMN1/SMN2 ratio of 1/3. This finding supports the idea that deletion rather than conversion is the main genetic event in type I spinal muscular atrophy. In addition, the ratio of SMN1/SMN2 among Japanese carriers, which was thought to be higher than that of the Western population, was compatible with the results obtained in Western populations. For further insight into the characteristic genetic background of spinal muscular atrophy in Japanese, determination of the gene copy number is essential.
Intragenic telSMN mutations: Frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number
1998, American Journal of Human Genetics
The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in ∼95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3′ end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5′ UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number.
Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMN(T) and SMN(C) gene copy number
1997, American Journal of Human Genetics
The survival motor neuron (SMN) transcript is encoded by two genes, SMN^T and SMN^C. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMN^T gene. The SMN^T gene can be distinguished from the SMN^C gene by base-pair changes in exons 7 and 8. SMN^T exon 7 is not detected in ∼95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMN^T now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMN^T, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMN^T and SMN^C gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMN^T copy number.
When is a deletion not a deletion? When it is converted
1997, American Journal of Human Genetics
The gene for human glutaredoxin (GLRX) is localized to human chromosome 5q14
1996, Genomics
Glutaredoxin is a small protein (12 kDa) catalyzing glutathione-dependent disulfide oxidoreduction reactions in a coupled system with NADPH, GSH, and glutathione reductase. A cDNA encoding the human glutaredoxin gene (HGMW-approved symbol GLRX) has recently been isolated and cloned from a human fetal spleen cDNA library. The screening of a human genomic library in Charon 4A led to the identification of three genomic clones. Using fluorescencein situhybridization to metaphase chromosomes with one genomic clone as a probe, the human glutaredoxin gene was localized to chromosomal region 5q14. This localization at chromosome 5 was in agreement with the somatic cell hybrid analysis, using DNA from a human–hamster and a human–mouse hybrid panel and using a human glutaredoxin cDNA as a probe.

View all citing articles on Scopus

View full text

Article preview

Genomics

References (18)

Linkage analysis of spinal muscular atrophy

Genomics

Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12–q14

Lancet

Classification of spinal muscular atrophies

Lancet

A PstI polymorphism at the D5S39 locus

Nucleic Acids Res.

Report of the committee on the genetic constitution of chromosome 5

Cytogenet. Cell Genet.

Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3

Nature

Report of the committee on methods of linkage analysis and reporting

Cytogenet. Cell Genet.

Muscle Disorders in Childhood

Genetic homogeneity between acute and chronic forms of spinal muscular atrophy

Nature

Cited by (24)

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2

The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy

Intragenic telSMN mutations: Frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number

Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMN(T) and SMN(C) gene copy number

When is a deletion not a deletion? When it is converted

The gene for human glutaredoxin (GLRX) is localized to human chromosome 5q14

Short CommunicationLinkage study of chronic childhood-onset spinal muscular atrophy (SMA): Confirmation of close linkage to D5S39 in French Canadian families

Genomics

Lancet

Lancet

A PstI polymorphism at the D5S39 locus

Nucleic Acids Res.

Report of the committee on the genetic constitution of chromosome 5

Cytogenet. Cell Genet.

Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3

Nature

Report of the committee on methods of linkage analysis and reporting

Cytogenet. Cell Genet.

Muscle Disorders in Childhood

Genetic homogeneity between acute and chronic forms of spinal muscular atrophy

Nature

Short Communication
Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): Confirmation of close linkage to D5S39 in French Canadian families