A Novel ZRS Mutation Leads to Preaxial Polydactyly Type 2 in a Heterozygous Form and Werner Mesomelic Syndrome in a Homozygous Form

ABSTRACT Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation. Sequencing of two Mexican families that have a variable limb malformation phenotype that includes polydactyly, triphalangeal thumb and one individual with Werner mesomelic syndrome (WMS) found a novel mutation in the zone of polarizing activity regulatory sequence (ZRS). This mutation, ZRS402, leads to an expansion of the enhancer expression in mouse embryonic limbs. The individual with WMS is the only one who is homozygous for this mutation, suggesting a dosage effect for this ZRS mutation.