An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica

Acrodermatitis enteropathica (AE) is a very rare inherited recessive disease caused by severe zinc deficiency. It typically occurs in early infancy and is characterized by periorificial and acral dermatitis, alopecia, and diarrhea. In 2002, both we and others identified the AE SLC39A4 gene located at 8q24.3, and described the first causative mutations for the disease. The SLC39A4 gene encodes a zinc-specific transporter belonging to the Zinc/Iron-regulated transporter-like family, which is highly expressed in the duodenum and jejunum. The SLC39A4 mutations are spread over the entire gene and include many different types of mutations. We report here the identification of five novel variants, including three likely pathogenic mutations. Since the first description, 31 mutations or unclassified variants of SLC39A4 have been reported in this gene. Although most of the patients with AE carry homozygous or compound heterozygous mutations, some of them have either no SLC39A4 mutation or only a monoallelic mutation. Thus, a genotype-phenotype correlation is not easily defined for all AE patients, and the molecular basis of the disease could be more complex than previously described. In cases unexplained by current genetic analyses, the most plausible molecular causes could be a dysregulation of the SLC39A4 gene transcription -- involving either metal response elements (MREs) or a modifier gene -- or the existence of another putative AE gene. In this review, we summarize the current knowledge of SLC39A4 mutations, as well as the future prospects to fully unravel the pathogenesis of AE.