HIGH-RESOLUTION PHYSICAL MAP OF THE REGION SURROUNDING THE SPINAL MUSCULAR-ATROPHY GENE

Spinal muscular atrophy (SMA) is the second most common lethal, autoso mal recessive disease in Caucasians, second only to cystic fibrosis. I n an effort to identify the causative gene in SMA, we have used radiat ion hybrid (RH) mapping to prepare a high resolution physical map of t he proximal region of chromosome 5 (5q11-13) which contains the SMA ge ne. The map of the SMA region, which spans approximately 4 Mb, contain s 19 loci including 9 polymorphic DNA markers, 8 monomorphic sequence tagged sites (STS) and two genes. Based upon the RH map the two polymo rphic loci which most closely flank the SMA locus were estimated to be separated by approximately 750 kb. Using two different directional cl oning schemes, several new clones between the genetic markers which mo st closely flank SMA were isolated. These new clones within the SMA ca ndidate region, together with cosmid clones prepared from one RH hybri d which retains an approximately 1 Mb segment spanning the SMA region as its only human DNA, will greatly facilitate efforts to identify the gene for SMA. In addition, analysis of cloned DNA segments from withi n the SMA candidate region has identified the presence of a novel, chr omosome 5-specific, low copy repeated sequence which is distributed th roughout the region containing the SMA gene as well as in at least fou r other regions of chromosome 5. Whether or not these novel repeated s equences throughout the SMA region are involved in the disease remains to be determined.