Genomic localization, organization and amplification of the human zinc transporter protein gene, ZNT4, and exclusion as a candidate gene in differentclinical variants of acrodermatitis enteropathica

Acrodermatitis enteropathica is an inherited disorder of zinc metabolism, t he molecular basis of which is currently unknown. Recent transgenic mouse s tudies have highlighted the potential significance of certain zinc transpor t proteins, for example ZnT4, in providing clues to the pathogenesis of zin c-related disorders such as acrodermatitis enteropathica. Specifically, mic e of any genotype suckled on ZnT4-deficient mice fail to absorb intestinal zinc and ZnT4-deficient mice also develop dermatitis, alopecia and stunted growth. Therefore, to assess human ZnT4 as a candidate gene/protein in acro dermatitis enteropathica or related disorders, we characterized the intron- exon organization of the human ZNT4 gene, which comprises seven distinct ex ons spanning approximately 38.7 kb. High-resolution radiation hybrid mappin g placed ZNT4 on, 15q21.1. We also developed a PCR-based mutation detection strategy using primers placed on flanking introns followed by direct seque ncing of the PCR products. Using this approach, we sequenced DNA from five individuals with acrodermatitis enteropathica; no mutations were identified . Thus, ZNT4 is unlikely to be the correct candidate gene for this disorder . We also identified and characterized two common single nucleotide polymor phisms in exon 5 and in the 3' UTR of ZNT4, which will be useful for future genetic linkage studies in assessing ZNT4 as a candidate gene for other in herited disorders of zinc metabolism.