LARGE LINKAGE ANALYSIS IN 100 FAMILIES WITH AUTOSOMAL RECESSIVE SPINAL MUSCULAR-ATROPHY (SMA) AND 11 CEPH FAMILIES USING 15 POLYMORPHIC LOCI IN THE REGION 5Q11.2-Q13.3

The autosomal recessive proximal spinal muscular atrophy (SMA) gene wa s mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 1 4 polymorphic simple sequence repeats (SSRs) and one RFLP in the regio n 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z(max) = 27.94. Two recombina nts were identified between the SMA gene and the closest telomeric mar ker D5S557 (theta = 0.02 at z(max) = 8.63). The first places the SMA g ene centromeric to this marker; the second suggests a double recombina nt at D5S557, which is very unlikely. More likely explanations are dis cussed in the paper. No recombinant was found between D5S435 and the S MA gene (theta = 0.00 at z(max) = 25.36). We localized a recently desc ribed polymorphic marker, D5S351 (Hudson et al., 1992), close to the S MA (theta = 0.00 at z(max) = 19.01) and the 3'MAP1B gene (theta = 0.01 at z(max) = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat , D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S 682/C88.3GT). These markers are too far from the SMA gene to be releva nt for cloning; nevertheless, as part of the human genome project, the y are contributing to the fine genetic mapping of the region 5q11.2-q1 3.3. The most likely order of the loci based on two-point and multipoi nt linkage analyses as well as on specific recombination events and ph ysical mapping studies is -3'MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5 S682). In general, the genetic distances obtained from the SMA and CEP H families are comparable. (C) 1994 Academic Press, Inc.