An update on mutations of theSLC39A4gene in acrodermatitis enteropathica

Abstract

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.

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…Zinc-deficient phenotypes in AE patients can be ameliorated with a simple, daily oral zinc supplementation (1-3 mg·kg Ϫ1 ·day Ϫ1 ) (362). ZIP4 is now the only zinc transporter indispensable for the uptake of zinc from the intestinal lumen, but some AE mutations, which are not linked to the chromosomal region of the ZIP4/SLC39A4 gene by homozygous mapping, are present (362,432). Thus another ZIP transporter may operate as a second zinc uptake route in the digestive tract.…”

Development of the First Fluorescence Screening Assay for the SLC39A2 Zinc Transporter

“…Mutations in the gene of SLC39A4 (ZIP4) have been shown to be associated with the disease acrodermatitis enteropathica, 6 and malfunction due to genetic alterations of other ZIP proteins has already been implicated in many other diseases.…”

Acquired zinc-deficiency in a premature neonate

“…A kórkép igen ritka (prevalencia: 1:500000), autoszomális recesszív öröklésmenetet mutat; a cink felszívó-dás zavarát a főleg a duodenum és a jejunum enterocytában, valamint a vesében expresszálódó SLC39A gén által kódolt Zip4 cink transzporter fehérje genetikai defetusa idézi elő (8q24.3 locus) (2). A cink a szervezet számára nélkülözhe-tetlen, esszenciális nyomelem, közel 1000 metallo-enzim al-51…”