IDENTIFICATION OF A CANDIDATE MODIFYING GENE FOR SPINAL MUSCULAR-ATROPHY BY COMPARATIVE GENOMICS

Spinal muscular atrophy (SMA) is a common recessive disorder character ized by the loss of lower motor neurons in the spinal cord. The diseas e has been classified into three types based on age of onset and sever ity(1). SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly al l patients display deletions or gene conversions of the survival motor neuron (SMN1) gene(4-7). Some correlation has been established betwee n SMN protein levels and disease course(8-10): nevertheless, the genet ic basis for SMA phenotypic variability remains unclear, and it has be en postulated that the loss of an additional modifying factor contribu tes to the severity of type I SMA. Using comparative genomics to scree n for such a factor among evolutionarily conserved sequences between m ouse and human, we have identified a novel transcript, H4F5, which lie s closer to SMN? than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of t ype I SMA chromosomes is embedded in an intron of this gene, indicatin g that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.