We studied six new DD-affected families using two-point lod score analysis of DAR in relation to polymorphic loci in the 12q23–24.1 region. These six families had positive lod scores for the marker D12S105 () similar to the 10 families that we originally studied (Ikeda et al, 1994
). The Cd family had a single recombinant between DAR and D12S105, giving this family a negative lod score of −5.55 at θ
= 0. This resulted in a combined two-point lod score of 26.42 at θ
= 0.01 for all 16 families. The maximum lod score was 30.08 at θ
= 0.0284 (SD = 0.0068).
Pairwise Lod Scores between DAR and D12S105 at the Indicated Recombinant Fractiona
Haplotype analysis of our families, using the microsatellite markers D12S105, D12S234, D12S129, and D12S354, has shown recombinants which further allow us to decrease the area containing DAR. In the Bo family, DAR is recombinant with the telomeric markers D12S129 and D12S354 () in III-4
, a 56-y-old unaffected female (examined by Y.S.). DAR also is recombinant with these same markers in an affected male in the previously reported Ba kindred (Ikeda et al, 1994
) (data not shown). shows an affected male (III-3
) in the Cd family, in whom DAR is recombinant with the centromeric markers D12S234 and D12S105. These results place DAR between D12S234 (cen) and D12S129 (tel).
Pedigrees showing genotypes and recombinants which localize DAR between flanking markers
Neuronal NOS1 has been localized by fluorescent in situ
hybridization to the 12q24.2–24.31 region, and a trinucleotide repeat polymorphism has been described within an intronic region of the gene (Twells et al, 1995
). We used this polymorphism to test whether NOS1 maps to the genetically delimited DAR region as a possible candidate gene for DAR. In using this polymorphism we have been able to localize NOS1 in relation to DAR and the microsatellite markers that flank DAR. As shown in , an affected male (III-7
) in the As family (Ikeda et al, 1994
) is recombinant between the more telomeric marker D12S79 and NOS1. shows the Be family (Ikeda et al, 1994
), which contains an affected male (III-4
) and an unaffected female (III-7
); both have recombinants between NOS1 and D12S354. These recombinants place NOS1 between D12S354 (cen) and D12S79 (tel), telomeric to the D12S234–D12S129 interval containing DAR.
Pedigrees showing genotypes and recombinants which localize NOS1 between flanking markers
These findings further sublocalize DAR () and make physical mapping a more practical pursuit. In addition, our localization of DAR to 12q23–24.1 of an additional six families brings us to 37 as the total number of kindreds reported with this localization, suggesting that alterations in a single gene mapping to this region are responsible for DD. Haplotype analysis of our families with the NOS1 polymorphism allowed us to exclude NOS1 as a candidate gene for DD. Further studies will emphasize the construction of a contig for this region studies of new families and identification of epidermal-specific transcripts to identify the DD gene.
Map showing the localization of DAR and NOS1 in relation to various microsatellite markers