Identification and characterization of a spinal muscular atrophy-determining gene.
Spinal muscular atrophy (SMA) is a common fatal autosomal recessive disorder characterized by degeneration of lower motor neurons, leading to progressive paralysis with muscular atrophy. The gene for SMA has been mapped to chromosome 5q13, where large-scale deletions have been reported. We describe here the inverted duplication of a 500 kb element in normal chromosomes and narrow the critical region to 140 kb within the telomeric region. This interval contains a 20 kb gene encoding a novel protein of 294 amino acids. An highly homologous gene is present in the centromeric element of 95% of controls. The telomeric gene is either lacking or interrupted in 226 of 229 patients, and patients retaining this gene (3 of 229) carry either a point mutation (Y272C) or short deletions in the consensus splice sites of introns 6 and 7. These data suggest that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.
Lefebvre
S
S
Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale, Institut Necker, Hôpital des Enfants Malades, Paris, France.
Bürglen
L
L
Reboullet
S
S
Clermont
O
O
Burlet
P
P
Viollet
L
L
Benichou
B
B
Cruaud
C
C
Millasseau
P
P
Zeviani
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D002895:Chromosomes, Human, Pair 5; D017362:Cyclic AMP Response Element-Binding Protein; D016521:Electrophoresis, Gel, Pulsed-Field; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012326:RNA Splicing; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*; D016615:Telomere
D017362:Cyclic AMP Response Element-Binding Protein; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins