rs121434289 — SLC39A4 Gly374Arg

ZIP4 Loss of Function — When the Zinc Gate Stays Shut

Every cell in your body requires zinc, but none more acutely than the enterocytes lining the duodenum and proximal jejunum. These cells express ZIP4, a protein encoded by SLC39A4 that acts as the primary gateway for dietary zinc absorption. When ZIP4 functions normally, it sits on the apical membrane of gut cells and actively imports zinc from food into the bloodstream. The Gly374Arg variant disrupts this gateway completely — the protein misfolds, never reaches the cell surface, and the body is left unable to absorb zinc through its normal intestinal route.

The Mechanism

The glycine at position 374 sits within the ZIP-family variable region of the transmembrane domain, a stretch conserved across zinc transporters because it is critical for correct protein folding. Replacing glycine — the smallest amino acid, with no side chain — with the bulky, positively-charged arginine introduces steric and electrostatic clashes that destabilize the transmembrane architecture. Functional studies in HEK293 cells¹¹ Functional studies in HEK293 cells
Wang et al., Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet, 2004 showed that Gly374Arg retains immature glycosylation patterns, indicating the protein is trapped in the endoplasmic reticulum and never completes transit to the plasma membrane. The result is total loss of zinc uptake activity — not a partial reduction, but a complete block.

The Evidence

Acrodermatitis enteropathica (AE) is a rare autosomal recessive disease with a global incidence of approximately 1 in 500,000 newborns²² 1 in 500,000 newborns
StatPearls: Acrodermatitis Enteropathica, NCBI Bookshelf. The SLC39A4 gene was identified as the cause in 2002 when Küry et al. sequenced 8 affected families³³ Küry et al. sequenced 8 affected families
Küry S et al., Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet, 2002 and found the Gly374Arg substitution in homozygous form in one affected male. Subsequent mutation surveys have catalogued over 30 pathogenic SLC39A4 variants; Küry et al. 2003⁴⁴ Küry et al. 2003
Küry S et al., Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Hum Mutat, 2003 expanded the catalog to 21 mutations across 26 pedigrees, establishing that missense variants in transmembrane glycine positions are a recurrent disease mechanism.

The clinical phenotype is distinctive: affected homozygotes develop a triad of periorificial and acral dermatitis (sharply demarcated, crusted, psoriasiform plaques around the mouth, anus, and extremities), chronic diarrhea, and alopecia — typically within weeks of weaning from breast milk. Serum zinc falls below 70 µg/L. Secondary infections with Staphylococcus aureus and Candida are common. Without treatment, untreated AE is lethal within the first years of life.

Critically, the prognosis with treatment is excellent: zinc supplementation at 3 mg/kg/day of elemental zinc produces 100% symptomatic resolution, typically within one to three weeks, with complete normalization of skin, hair, and gastrointestinal findings. Schmitt et al. 2009⁵⁵ Schmitt et al. 2009
Schmitt S et al., An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Int J Dermatol, 2009 reviewed long-term outcomes and emphasized that supplementation must continue lifelong because the underlying transport defect is permanent.

Practical Actions

Carriers (one T allele) have one functional ZIP4 copy and absorb zinc normally under ordinary dietary conditions. No zinc supplementation is needed for carriers. However, knowledge of carrier status has family-screening implications: two carrier parents face a 1-in-4 risk with each pregnancy of having an affected child. Homozygotes require lifelong monitored zinc therapy; the key risks are zinc toxicity from over-supplementation and secondary copper depletion, as high zinc levels competitively inhibit intestinal copper absorption via metallothionein upregulation.

Interactions

The Gly374Arg variant causes full loss of ZIP4 function. Other pathogenic SLC39A4 variants (frameshift, splice-site, nonsense) also abolish transport; an individual who carries Gly374Arg on one allele and a different loss-of-function SLC39A4 variant on the other (compound heterozygous) is equally affected as a homozygote. Related population-common variation in SLC39A4 exists at rs1871534 (Leu372Val), which produces a mild reduction in zinc transport and shows extreme population stratification (near-fixation in West Africa); this common variant does not cause AE but may modestly affect zinc homeostasis in the context of dietary deficiency.