Homozygosity mapping of an acromesomelic dysplasia on chromosome 9. P. Ianakiev¹, M.W. Kilpatrick¹, M.J. Daly², A. Zolindaki¹, D. Bagley⁴, G. Beighton³, P. Beighton³, P. Tsipouras¹. 1) Pediatrics, UConn Health Center, Farmington, CT; 2) Whitehead Institute, Cambridge, MA; 3) University of Cape Town, South Africa; 4) Principal Medical Officer, St Helena.

   The Acromesomelic Dysplasias (AMD) are a group of autosomal recessive disorders that primarily affect the middle and distal segment of the extremities. Homozygosity mapping is potentially a powerful approach for mapping rare recessive traits in inbred populations. The island of St. Helena in the South Atlantic has a population of 5,500 derived from a discrete number of founders. DNA from 15 members of four related nuclear families segregating an AMD was collected for gene mapping. The phenotype was characterised by dwarfism, mesomelic limb shortening and gross distortion of the digits. Genetic linkage to the CDMP-1 locus on chromosome 20 that has been shown to be mutated in both Grebe and Hunter-Thompson types of AMD was excluded using markers flanking CDMP-1. Six consecutive chromosome 9 markers, spanning approximately 5 cM showed identical homozygosity in all affected individuals thus identifying a region of homozygosity by descent. Multipoint analysis generated a maximum lod score of 2.85. These data localize the gene for this dysplasia to the pericentromeric region of chromosome 9. This localization overlaps with the recently defined critical region for the Maroteaux type of AMD (AMDM). The phenotype of the St. Helena type of AMD shares some features with AMDM but also includes additional features. A number of genes have been localized to the pericentromeric region of chromosome 9 including the forkhead domain containing FKHL9 gene, IL11RA which has been shown to be expressed in skeletal progenitor cells during murine development and BAG1 which has been shown to enhance growth factor-mediated protection from apoptosis. This study demonstrates the power of homozygosity mapping in the rapid localization of recessive traits. Only four affected individuals generated a lod score of 2.85. The identification of the gene responsible for this disorder may shed further light on the extent of heterogeneity within the AMDs and on the complex processes involved in limb morphogenisis.