CONSTRUCTION OF A HIGH-RESOLUTION LINKAGE MAP FOR XP22.1-P22.2 AND REFINEMENT OF THE GENETIC LOCALIZATION OF THE COFFIN-LOWRY SYNDROME GENE

The genes responsible for two X-linked diseases, the Coffin-Lowry synd rome (CLS) and juvenile retinoschisis (RS), have been previously mappe d, through linkage studies, to an 8-cM region, in Xp22.1-p22.2, flanke d distally by two tightly linked markers, DXS207 and DXS43, and proxim ally by DXS274. In the present study, five Genethon markers have been assigned to the (DXS207, DXS43)-DXS274 interval using somatic cell hyb rids and a meiotic breakpoint panel and ordered together with three ma rkers previously mapped to this region. A genetic map, which includes 13 loci and spans a distance of approximately 13 cM, was derived from linkage analysis using the CEPH families. The most likely locus order and map distances (in centimorgans) are Xpter-DXS16-(3.4)-(DXS207, DXS 43, DXS1053)-(2.0)-(DXS999, DXS257)-(1.7)-AFM291wf5-(1.4) - DXS443 - ( 2.0) - (DXS1229, DXS365) - (2.1) - (DXS1052, DXS274, DXS41)-Xcen. Anal ysis of multiply informative crossovers established AFM291wf5 and DXS1 052 as new flanking markers for CLS, which significantly reduces the c andidate region for this disease gene to a 4- to 5-cM interval. Three markers, DXS443, DXS1229, and DXS365, mapping within this interval sho wed complete cosegregation with the disease phenotype, giving a multip oint lod score of 14.2. The present map provides the framework for con structing a YAC contig for the CLS and RS region and should be useful for refining the localization of other disease genes mapping to this r egion. The panel of somatic cell hybrids characterized for the present study has also allowed us to refine the localization of five genes (C ALB3, GRPR, PDHA1, GLRA2, and PHKA2) and two expressed sequence tags ( DXS1118E and DXS1006E) previously assigned to the Xp22 region. (C) 199 4 Academic Press, Inc.