SLC39A4 – Acrodermatitis Enteropathica

Acrodermatitis enteropathica (AE) is a rare autosomal recessive disorder characterized by periorificial and acral dermatitis, alopecia, and diarrhea due to impaired intestinal zinc uptake. The SLC39A4 gene (SLC39A4) encodes the ZIP4 zinc transporter; loss-of-function variants in SLC39A4 underlie AE by abolishing ZIP4-mediated zinc absorption in enterocytes (PMID:20300938). Genetic confirmation is essential for diagnosis and guiding lifelong zinc supplementation therapy.

1 Clinical Validity

The SLC39A4–AE association is classified as Definitive. Over 100 probands from >14 unrelated families have been reported with biallelic pathogenic variants, consistent autosomal recessive inheritance, and segregation in multiplex pedigrees. Segregation of ZIP4 variants with disease has been observed in multiple siblings in both twin studies and consanguineous families.

2 Genetic Evidence

Inheritance: Autosomal recessive. Segregation: at least 4 affected relatives in multiplex families (two siblings in a Chinese twin report; two siblings in a Saudi family) tracked with SLC39A4 variants.
Case series: 15 patients across two Japanese families with three novel mutations (PMID:12787121); dozens of additional single and multi-patient reports worldwide.
Variant spectrum: >45 distinct SLC39A4 variants including missense (e.g., c.283C>T (p.Arg95Cys)), nonsense, splice-site (c.1287+2T>C), insertions (c.1191insC), and duplications (c.541_551dup). Founder alleles noted in Sierra Leone (1191insC) and Tunisia (c.143T>G).
Representative variant: c.1115T>G (p.Leu372Arg) identified homozygously in a Chinese patient with classic AE manifestations (PMID:20300938).

3 Functional Evidence

Functional assays in mouse and human systems demonstrate that AE-associated missense variants (e.g., p.Pro200Leu, p.Gly374Arg) drastically reduce ^65Zn uptake, disrupt ZIP4 cell surface localization, and abrogate zinc-responsive trafficking (PMID:14709598; PMID:33837739). Structural studies of the ZIP4 extracellular domain clarify how pathogenic mutations impair dimerization and zinc binding critical for transport (PMID:27321477).

4 Conflicting Evidence

No robust evidence challenges the SLC39A4–AE link; transient zinc deficiency without SLC39A4 mutations is distinguished clinically by genetic testing.

5 Conclusion

Extensive genetic and functional data establish a definitive autosomal recessive association between SLC39A4 and acrodermatitis enteropathica. Genetic testing of SLC39A4 is recommended in infants with the clinical triad of dermatitis, alopecia, and diarrhea to confirm diagnosis and initiate zinc therapy promptly.

Key Take-home: Biallelic SLC39A4 variants cause AE via ZIP4 loss of function; genetic confirmation enables life-saving zinc supplementation.

References

• Archives of dermatological research • 2010 • One novel homozygous mutation of SLC39A4 gene in a Chinese patient with acrodermatitis enteropathica. PMID:20300938
• The Journal of investigative dermatology • 2003 • Novel SLC39A4 mutations in acrodermatitis enteropathica. PMID:12787121
• Human molecular genetics • 2004 • Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. PMID:14709598
• Human mutation • 2021 • Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking. PMID:33837739
• Nature communications • 2016 • Structural insights of ZIP4 extracellular domain critical for optimal zinc transport. PMID:27321477

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