title: A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 (survival motor neuron) gene. It is classified by age of onset and maximal motor milestones achieved in type I, II, and III (severe, intermediate, and mild form, respectively). Of 369 unrelated SMA patients who were investigated for homozygous deletions in the SMN1 gene, 18 patients (4.8%) revealed at least one copy of exon 7. A 4-bp deletion in exon 3 (c.399_402delAGAG) was detected in 15 patients from 10 families. This mutation was associated with a large spectrum of phenotypes from type I to asymptomatic patients. Five patients from two consanguineous families were homozygous for the mutation with diverse mild phenotypes. Determination of the SMN2 copy number showed that the presence of two or three copies generally correlated with a better evolution. RT-PCR studies of SMN transcripts in control and patients with the same SMN2 copy number showed that the full-length/Delta7 ratio is influenced by the SMN1 genotype although it seems independent of the SMN2 copy number. Moreover, protein analysis in these patients showed a reduction in SMN protein in compound heterozygous patients (c.399_402delAGAG/deletion) when compared with homozygous c.399_402delAGAG/c.399_402delAGAG patients. Microsatellite DNA markers flanking the SMA locus revealed the occurrence of the 4-bp deletion in the background of the same haplotype, suggesting that a single mutational event was involved in the 10 families. The geographic origins of ancestors point to a founder effect from the south and east of Spain. The c.399_402delAGAG, which is to date unique to the Spanish population, constitutes the most frequently found subtle mutation in SMA. Hum Mutat 22:136-143, 2003.
authors.affiliation: Hospital de Sant Pau, Genetics and Research Institute, Barcelona, Spain.
authors.forename: Ivon
authors.initials: I
authors.lastname: Cuscó
authors.forename: Eva
authors.initials: E
authors.lastname: López
authors.forename: Carolina
authors.initials: C
authors.lastname: Soler-Botija
authors.forename: María
authors.initials: M
authors.lastname: Jesús Barceló
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Tizzano
mesh_terms: D000225:Adenine / Q000378:metabolism*; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein; D005260:Female; D005838:Genotype; D006147:Guanine / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D017384:Sequence Deletion / Q000235:genetics*; D013030:Spain; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D006147:Guanine; D000225:Adenine