title: Characterisation of SMN hybrid genes in Spanish SMA patients: de novo, homozygous and compound heterozygous cases.
abstract: Autosomal recessive spinal muscular atrophy (SMA) is classified, by age of onset and maximal motor milestones achieved, into type I (severe form), type II (intermediate form) and type III (mild/moderate form). SMA is caused by mutations in the survival motor neuron telomeric gene (SMN1) and a centromeric functional copy of this gene (SMN2) exists, both genes being located at 5q13. Homozygous deletion of exons 7 and 8 of SMN1 has been detected in approx 85% of Spanish SMA patients regardless of their phenotype. Nineteen cases with the sole deletion of exon 7 but not exon 8 (2 cases of type I, 13 cases of type II, four cases of type III) were further analysed for the presence of SMN2-SMN1 hybrid genes. We detected four different hybrid structures. Most of the patients were carriers of a hybrid structure: centromeric intron 6- centromeric exon 7- telomeric exon 8 (CCT), with or without neuronal apoptosis-inhibitor protein (NAIP). In two patients, a different hybrid structure, viz. telomeric intron 6- centromeric exon 7- telomeric exon 8 (TCT), was detected with or without NAIP. A phenotype-genotype correlation comparing the different structures of the hybrid alleles was delineated. Type I cases in our series are attributable to intrachromosomal deletion with a smaller number of SMN2 copies. Most cases with hybrid genes are type II occurring by a combination of a classical deletion in one chromosome and a hybrid gene in the other. Type III cases are closely associated with homozygozity or compound heterozygozity for hybrid genes resulting from two conversion events and have more copies of hybrid genes and SMN2 than type I or II cases.
authors.affiliation: Servei de Genètica, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Cuscó
authors.forename: M J
authors.initials: MJ
authors.lastname: Barceló
authors.forename: E
authors.initials: E
authors.lastname: del Rio
authors.forename: Y
authors.initials: Y
authors.lastname: Martín
authors.forename: C
authors.initials: C
authors.lastname: Hernández-Chico
authors.forename: E
authors.initials: E
authors.lastname: Bussaglia
authors.forename: M
authors.initials: M
authors.lastname: Baiget
authors.forename: E F
authors.initials: EF
authors.lastname: Tizzano
mesh_terms: D000483:Alleles; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051616:Neuronal Apoptosis-Inhibitory Protein; D010375:Pedigree; D010641:Phenotype; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; 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; C496800:NAIP protein, human; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; 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; D004247:DNA