The genetic factors involved in type I1 diabetes are still unknown. To address this problem, we are creating a I0 to 15; cM genetic map on 444 individuals from 32 Mexican American families ascertained on a type !I diabetic proband. Using highly polymorphic microsatellite markers and a multipoint variance components method, we found evidence for linkage of plasma glucose concentration 2 hr after oral glucose administration to two regions on chromosome I1: Ig-hemoglobin (HBB} and markers DllS899/DIISI324 near the sulfonylurea receptor (SUR) gene. lod scores at these two loci were 2.77 and 3.37, respectively. The SUR gene region accounted for 4-4.7% of the phenotypic variance. Evidence for linkage to fasting glucose concentration was also observed for two loci on chromosome 6, one of which is identical to a proposed susceptibility locus for type I diabetes {D6S290). When diabetics were excluded from the analyses, all lod scores became zero, suggesting that the observed linkages were with the trait diabetes rather than with normal variation in glucose levels. Results were similar whether all diabetics were included in the analyses or only those who were not under treatment with oral antidiabetic agents or insulin.

Acheiropodia is an autosomal recessive disease that results in hemimelia (lack of formation of the distal extremities). We performed a complete genome screen of seven members of an extended pedigree that included three siblings with acheiropodia. Homozygosity mapping was used to identify regions most likely to harbor the gene for acheiropodia in this pedigree. In these two key regions (14p and 7q), further genotyping of one additional affected member of this pedigree plus seven additional unaffected siblings provided evidence, through linkage analysis, that the 7q36 region contains the acheiropodia gene. In this region, a maximum two-point LOD score of 3.81 (4.2 with multipoint analysis) was achieved, and a homozygous haplotype spanning a region of 11.7 cM was seen in all affected in this pedigree. Finally, genotypic analysis of two additional cases of acheiropodia with no known relation to the other samples revealed homozygous sharing of a portion of the same haplotype on 7q36, which reduces the chromosomal location of the acheiropodia gene to an 8.6-cM region. Localization of this gene, at the screening level, by use of data from only three affected subjects, provides an example of how certain genes may be mapped by use of a minimal number of affected cases.