A HUMAN MSX1 HOMEODOMAIN MISSENSE MUTATION CAUSES SELECTIVE TOOTH AGENESIS

We demonstrate that a mutation in the homeobox gene, MSX1, causes a co mmon developmental anomaly, familial tooth agenesis. Genetic linkage a nalyses in a family with autosomal dominant agenesis of second premola rs and third molars identified a locus on chromosome 4p, where the MSX 1 gene resides. Sequence analyses demonstrated an Arg31Pro missense mu tation in the homeodomain of MSX1 in all affected family members. Arg 31 is a highly conserved homeodomain residue that interacts with the r ibose phosphate backbone of target DNA. We propose that the Arg31 Pro mutation compromises MSX1 interactions, and suggest that MSX1 function s are critical for normal development of specific human teeth.