RESUMO
Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity. SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly all patients display deletions or gene conversions of the survival motor neuron (SMN1) gene. Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.
Assuntos
Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Clonagem Molecular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Deleção de Genes , Marcadores Genéticos , Homozigoto , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA , Proteínas do Complexo SMN , Homologia de Sequência de Aminoácidos , Proteína 1 de Sobrevivência do Neurônio MotorRESUMO
A mouse locus called Lgn1 determines differences in macrophage permissiveness for the intracellular replication of Legionella pneumophila. The only regional candidate genes for this phenotype difference lie within a cluster of closely linked paralogs of the Neuronal Apoptosis Inhibitory Protein (Naip) gene. Previous genetic and physical mapping of the Lgn1 phenotype narrowed it to an interval containing only Naip2 and Naip5, suggesting that there is not complete functional overlap among the mouse Naip loci. In order to gather more information about polymorphisms among the Naip genes of the 129 mouse haplotype, we have determined the genomic sequence of a substantial portion of the 129 Naip gene array. We have constructed an evolutionary model for the expansion of the Naip gene array from a single progenitor Naip gene. This model predicts the presence of two distinct families of Naip paralogs: Naip1/2/3 and Naip4/5/6/7. Unlike the divergences among all the other Naip paralogs, the splits among Naip4, Naip5, Naip6, and Naip7 occurred relatively recently. The high degree of sequence conservation within the Naip4/5/6/7 family increases the likelihood of functional overlap among these genes.