rs200482978 — SLC39A4

ZIP4 Trp401Ter — A Truncating Mutation in Acrodermatitis Enteropathica

Every milligram of zinc your body uses must be freshly absorbed from food — there are no meaningful zinc stores to fall back on. The gateway is a twelve-pass transmembrane protein called ZIP4¹¹ ZIP4
Zinc/Iron Regulated Transporter-related Protein 4 — the product of SLC39A4 on chromosome 8q24.3. ZIP4 is expressed at the apical surface of enterocytes in the duodenum and proximal jejunum, where it imports zinc from the gut lumen into intestinal cells, expressed densely on the absorptive face of duodenal enterocytes. When ZIP4 is missing or non-functional, dietary zinc cannot cross the intestinal wall in meaningful quantities — and the resulting whole-body zinc deficiency unfolds rapidly and severely.

The c.1203G>A variant (rs200482978 — see note) introduces a premature stop codon at position 401 of the 647-residue ZIP4 protein (p.Trp401Ter). The resulting truncated protein lacks the final seven transmembrane helices that form the zinc-conducting channel and is expected to be completely non-functional. Two copies of pathogenic SLC39A4 variants — either homozygous or compound heterozygous — cause acrodermatitis enteropathica²² acrodermatitis enteropathica
AE — from Greek: acral (affecting extremities and face), dermatitis (skin inflammation), enteropathica (intestinal disease). First described by Brandt in 1936 and named by Danbolt and Closs in 1943. OMIM #201100 (AE), characterised by the triad of periorificial dermatitis, chronic diarrhea, and alopecia.

The Mechanism

ZIP4 transports zinc using an unusual mechanism: it couples zinc influx to proton influx, exploiting the pH gradient at the intestinal lumen surface. Functional studies³³ Functional studies
Hoch E et al. Elucidating the H⁺ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica. Int J Mol Sci, 2020 confirmed that wild-type ZIP4 acts as a H⁺-powered Zn²⁺ co-transporter — extracellular acidification (mimicking the lumen microenvironment) dramatically stimulates zinc uptake, whereas AE-linked mutations abolish this coupling entirely.

For a nonsense mutation such as p.Trp401Ter, the mechanism of loss-of-function is straightforward: the transcript is recognised as aberrant and degraded by nonsense-mediated mRNA decay⁴⁴ nonsense-mediated mRNA decay
NMD — a cellular quality-control mechanism that degrades mRNAs containing premature stop codons, preventing translation of truncated, potentially dominant-negative proteins, or if any truncated protein escapes, it lacks the transmembrane segments required for zinc conduction. Either way, zinc import through this allele is zero.

Structural studies⁵⁵ Structural studies
Kuliyev E et al. Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking. J Biol Chem, 2021 examining seven AE missense mutations in the ZIP4 extracellular domain found that all seven completely abolished zinc transport activity, with mutant protein accumulating in the endoplasmic reticulum rather than reaching the apical cell surface. Nonsense variants are expected to be at least as severe as the worst missense variants.

The Evidence

SLC39A4 was identified as the sole gene for hereditary AE in 2002; since then over 80 distinct pathogenic variants have been reported. The Trp401Ter variant was first described by Küry et al. in 2003⁶⁶ Küry et al. in 2003
Küry S et al. Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Hum Mutat, 2003 in a compound heterozygous Austrian patient who also carried a known missense variant on the other SLC39A4 allele — demonstrating the classic biallelic inheritance pattern of AE. The ClinVar classification (Pathogenic; criteria provided, multiple submitters, no conflicts) reflects submissions from three independent clinical laboratories.

A comprehensive mutation survey⁷⁷ comprehensive mutation survey
Schmitt S et al. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat, 2009 documented 44 distinct pathogenic variants across all SLC39A4 exons, noting that most affected individuals are compound heterozygous rather than homozygous — a clinical insight that matters when interpreting biallelic carrier status.

AE untreated follows a predictable severe course: infants present within weeks of weaning with periorificial and acral dermatitis, profuse diarrhea, alopecia, failure to thrive, and immune dysfunction. Breastfed infants have a characteristically delayed onset because human milk contains a low-molecular- weight zinc ligand (not present in cow-milk formula) that enables some zinc absorption even without ZIP4 activity. Once weaning begins, this alternative route is lost and symptoms emerge. Without zinc replacement, AE can be fatal. With oral zinc supplementation, symptoms resolve within days and prognosis is excellent — though lifelong supplementation is mandatory.

Heterozygous Carriers

Heterozygous carriers have one functional and one non-functional ZIP4 allele. With 50% of ZIP4 protein at the apical surface, zinc absorption is maintained at adequate levels for normal health. Obligate heterozygote parents of AE patients — who have been studied across multiple case series — do not develop AE. Some evidence suggests that under high-zinc-demand states (illness, pregnancy, lactation, or sustained low dietary zinc) carriers may experience marginally reduced zinc absorption, though clinical zinc deficiency is not expected and has not been documented in phenotypically normal heterozygote carriers. The primary significance of carrier status is reproductive.

Practical Actions

Acrodermatitis enteropathica is autosomal recessive — clinical disease requires biallelic loss of ZIP4 function. For heterozygous carriers, the key action is reproductive counselling: if both parents carry a pathogenic SLC39A4 allele, each pregnancy has a 25% chance of biallelic AE. For homozygous or compound heterozygous individuals, prompt diagnosis and zinc supplementation are life-changing.

Interactions

AE is defined by biallelic SLC39A4 pathogenic variants. Compound heterozygosity — carrying two different pathogenic alleles (e.g. one missense and one nonsense like Trp401Ter) on opposite chromosomes — produces full AE just as homozygosity does. Clinicians should characterise both SLC39A4 alleles in any confirmed AE patient to enable accurate family cascade testing. Any other pathogenic SLC39A4 variant carried in trans with Trp401Ter produces biallelic disease; the compound action between this variant and any other pathogenic SLC39A4 allele follows the same zinc supplementation protocol as homozygosity.