Mapping of the Spinal Muscular
Atrophy (SMA) Gene to a 750-kb
Interval Flanked by Two New
Microsatellites

Wirth, Brunhilde; A, el-Agwany; Baasner, Anne; Burghes, Arthur H.M.; Koch, Armin; Dadze, A.; Piechaczeck-Wappenschmidt, B; Rudnik‐Schöneborn, Sabine; Zerres, Klaus; Schönling, Jutta

doi:10.1159/000472274

Cited by 23 publications

(14 citation statements)

References 13 publications

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“…Type III SMA (Kugelberg-Wlander disease, MIM# 253400) patients show first symptoms after 18 months and are able to stand and walk, but often become wheelchair-bound during youth or adulthood. The gene involved in type I-III SMA has been mapped to 5q12-q13 by linkage analysis, and refined to a region of about 750 kb Melki et al, 1990a, b;Gilliam et al, 1990;Wirth et al, 1995a]. The region contains a large inverted duplication consisting of at least four genes, which are present in a telomeric (t) and a centromeric (c) copy: survival motor neuron gene (SMN1 or SMNt and SMN2 or SMNc); neuronal apoptosis inhibitory protein gene (NAIP and ψNAIP); basal transcription factor subunit p44 (BTFp44t and BTFp44c); and a novel protein with unknown function H4F5t and H4F5c Roy et al, 1995;Bürglen et al, 1997;Carter et al, 1997;Scharf et al, 1998] (Fig.…”

Section: Introductionmentioning

confidence: 99%

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)

Wirth¹

2000

Hum. Mutat.

564

193

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Section: Introductionmentioning

confidence: 99%

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)

Wirth¹

2000

Hum. Mutat.

564

193

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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.…”

mentioning

confidence: 99%

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

Mailman

Heinz

Papp

et al. 2002

Genetics in Medicine

324

220

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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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“…Through the use of positional cloning and newly discovered polymorphic microsatellite markers this region was narrowed down to an inverted and duplicated genomic section of 500 kilo base-pairs in length, which contained multiple copies of several genes [21][22][23][24]. Two genes, the neuronal inhibitory protein (NAIP) gene and the survival of motor neuron (SMN) gene, were subject to large deletions in the majority of SMA patients [24][25][26].…”

Section: Genetic Basis Of Smamentioning

confidence: 99%

Applicability of Histone Deacetylase Inhibition for the Treatment of Spinal Muscular Atrophy

Lunke

El‐Osta

2013

Neurotherapeutics

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Spinal muscular atrophy (SMA), a neurodegenerative disease with potentially devastating and even deadly effects on affected individuals, was first described in the late nineteenth century. Although the survival of motor neuron (SMN) gene was identified nearly 2 decades ago to be causative of the disease, neither an effective treatment nor a cure are currently available. Yet efforts are on-going to test a multitude of treatment strategies with the potential to alleviate disease symptoms in human and clinical trials. Among the most studied compounds for the treatment of SMA are histone deacetylase inhibitors. Several of these epigenetic modifiers have been shown to increase expression of the crucial SMN gene in vitro and in vivo, an effect linked to increased histone acetylation and remodeling of the chromatin landscape surrounding the SMN gene promoter. Here, we review the history and current state of use of histone deacetylase inhibitors in SMA, as well as the success of clinical trials investigating the clinical applicability of these epigenetic modifiers in SMA treatment.

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Mapping of the Spinal Muscular Atrophy (SMA) Gene to a 750-kb Interval Flanked by Two New Microsatellites

Cited by 23 publications

References 13 publications

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)

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

Applicability of Histone Deacetylase Inhibition for the Treatment of Spinal Muscular Atrophy

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