GENETIC-HETEROGENEITY IN X-LINKED AMELOGENESIS IMPERFECTA

The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at θ = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multi-point linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at θ = 0, with a peak lod score in multipoint linkage analysis of 2.84 at θ = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9. Recombinations defined the localization of this second locus on the X chromosome causing XAI (AIH3) as Xq22-q28. This study demonstrates that there are at least two different loci on the X chromosome causing amelogenesis imperfecta, one on the distal short arm (AIH1) due to mutations in the AMELX gene and one on the long arm (AIH3) as a result of alterations in a gene in the Xq22-q28 region. © 1992 Academic Press, Inc. All rights reserved.