Refinement of the Spinal Muscular Atrophy Locus to the Interval between D5S435 and MAP1B

Vm, Soares; Lm, Brzustowicz; Kleyn, Patrick; Ja, Knowles; Da, Palmer; Asokan, Susha; Gk, Penchaszadeh; Tl, Munsat; Tc, Gilliam

doi:10.1006/geno.1993.1069

Cited by 53 publications

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“…[2][3][4][5][6][7][8][9][10][11][12] 5q-SMA has an incidence of 1/10,000 with an estimated carrier frequency of 1/50. [13][14][15][16][17] Deletion and gene conversion events result in a 95% to 98% rate of homozygous loss of the SMN1 gene in patients with classic SMA.…”

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

Mailman

Heinz

Papp

et al. 2002

Genetics in Medicine

312

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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. Genet Key Words: spinal muscular atrophy, SMN, polymerase chain reactionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by homozygous mutation of the SMN1 gene 1 on chromosome 5q13. 2-12 5q-SMA has an incidence of 1/10,000 with an estimated carrier frequency of 1/50. [13][14][15][16][17] Deletion and gene conversion events result in a 95% to 98% rate of homozygous loss of the SMN1 gene in patients with classic SMA. 1,18 -31 A further 1% to 3% of well-characterized SMA cases are the result of compound heterozygosity with an intragenic mutation and a deletion. 31,32 Clinically, SMA patients are classified as type I, II, or III, based on the severity of the disease and the age of onset. 33,34 SMA type I, also known as Werdnig-Hoffmann disease, 35,36 is the most severe presentation. Type I infants are hypotonic and have severe proximal muscle wasting due to a lack of ␣-motor neurons in the anterior horn of the spinal cord. These patients are diagnosed prenatally or within 6 months after birth. They never sit unaided and usually die within the first 2 years, most often due to respiratory muscle weakness. Patients with intermediate SMA type II develop the disease before 18 months of age. They are able to sit unaided, but do not stand or walk. SMA type III, also called Kugelberg-Welander disease, is less severe. 37,38 Type III patients are diagnosed after 18 months, are able to walk, can have children, and often live at least into the second or third decade. 39 This study presents the clinical experience of 6 years of SMA testing in the Molecular Pathology Laboratory at The Ohio State University. Despite the fact that more than 95% of 5q-linked SMA patients lack any intact SMN1, it has been our experience that Ͻ43% of patients ...

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confidence: 99%

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

Mailman

Heinz

Papp

et al. 2002

Genetics in Medicine

312

220

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“…Six site haplotypes were generated in seven nondeletion families and in two gene conversion families using markers in the SMA region. The following markers were used: D5S681 [Morrison et al, 1992], D5S435 [Soares et al, 1993], D5S610 [Thompson et al, 1993], D5S112 [Morrison et al, 1992], Map1B [Brzustowicz et al, 1992], and D5S127 [Sherrington et al, 1993], using published primers and reaction conditions. Forward primers were fluorescently labeled with ABI dyes such that all six systems could be analyzed in a single lane using the ABI377 automated DNA sequencer and the Genotyper computer software package.…”

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

et al. 1999

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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.

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“…Type I1 and I11 (chronic) SMA are milder forms and show onset of symptoms between six months and 17 years of age (Dubowitz, 1978). SMAs map to chromosome 5q13, within an interval of 400 kb, flanked by the polymorphic loci D5S435 and D5S557 (Soares et al, 1993;Francis et al, 1993). This interval encompasses also the SMA candidate region by linkage analysis of recombinant families (Burghes et al , 1994a).…”

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confidence: 98%

Deletion analysis of the simple tandem repeat loci physically linked to the spinal muscular atrophy locus

et al. 1996

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Multicopy dinucleotide repeats have been characterized in the spinal muscular atrophy (SMA) region on chromosome 5q13, which reveal deletions in some SMA patients. 119 Italian and Spanish SMA families have been analysed using the C272 and C212 markers. Seventy percent of these families were informative. We found 9.4% de novo deletions in SMA I and 1.5% in SMA II families. A single inherited deletion segregating in a Spanish pedigree was detected in three affected brothers. A SMA II patient showed deletion only of C272. The data presented in this study are relevant to the molecular diagnosis of SMA families in Italy and Spain and provide additional insights toward the understanding of the molecular pathology of SMA. © 1996 Wiley‐Liss, Inc.

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Refinement of the Spinal Muscular Atrophy Locus to the Interval between D5S435 and MAP1B

Cited by 53 publications

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

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

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

Deletion analysis of the simple tandem repeat loci physically linked to the spinal muscular atrophy locus

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