The SLC30A2 gene, encoding zinc transporter 2 (ZnT2), plays a crucial role in zinc transport from secretory vesicles into breast milk in mammary gland epithelial cells via the JAK2/STAT5 pathway (PMID: 19496757, 19494234).
SLC30A2 was first reported in relation to transient neonatal zinc deficiency (TNZD) in 2006 (Chowanadisai et al., PMID: 17065149). Affected infants are exclusively breastfed. Clinical manifestations include low serum zinc, skin lesions, dermatitis, erythema, alopecia, diarrhea, and failure to thrive, resembling acrodermatitis enteropathica (AE). Zinc supplements resolve symptoms without relapse after weaning. TNZD exhibits incomplete penetrance and variable expressivity, with some exclusively breastfed infants showing mild or no symptoms (PMID: 22733820). The condition typically follows an autosomal dominant inheritance pattern, though compound heterozygous and homozygous variants have been reported in mothers of early-onset TNZD infants (PMID: 23741301, 32278324). Eleven unique variants, including missense, nonsense, and frameshift mutations, documented in 13 unrelated mothers whose infants affected with TNZD across 10 publications (PMIDs: 17065149, 36967740, 22733820, 24194756, 24456035, 27304099, 28111782, 37082517, 23741301, 32278324) are included in this curation. The pathogenic mechanism involves loss-of-function through haploinsufficiency or dominant negative effects.
Experimental evidence further supports this gene-disease association. Knockout (KO) mice studies revealed higher cytoplasmic zinc levels in mammary gland cells compare to wildtype (WT) littermates, with altered zinc localization and accumulation (PMID: 25851903). These results are consistent with in vitro knockdown studies using siRNA in HC11 cells demonstrating cytoplasmic zinc trapping. In addition, ZnT2 null mice demonstrated reduction in milk zinc concentration and significantly lower litter survival (PMID: 25851903). Experimental studies on the TNZD associated variants including p.His54Arg, p.Gly87Arg, p.Gly280Arg, p.Thr312Met, p.Glu355Gln, p.Asp227Asn, p.Glu88Lys, p.Trp152Arg and p.Ser296Leu demonstrated various functional alterations including reduced zinc transport activity and secretion, zinc retention and mislocalization, decreased protein stability, and impaired dimerization in cell models (PMID: 17065149, 36967740, 22733820, 27137936, 23741301, 32278324). In addition, the c.838G>A p.Gly280Arg variant demonstrated aberrant splicing efficiency (PMID: 27304099).
In summary, there is definitive evidence to support the relationship between autosomal dominant loss of function variants in SLC30A2 and TNZD. This classification was approved by the This classification was approved by the ClinGen IEM GCEP on January 24, 2025 (SOP Version 11).
The SLC30A2 gene, encoding zinc transporter 2 (ZnT2), plays a crucial role in zinc transport from secretory vesicles into breast milk in mammary gland epithelial cells via the JAK2/STAT5 pathway (PMID: 19496757, 19494234).
SLC30A2 was first reported in relation to transient neonatal zinc deficiency (TNZD) in 2006 (Chowanadisai et al., PMID: 17065149). Affected infants are exclusively breastfed. Clinical manifestations include low serum zinc, skin lesions, dermatitis, erythema, alopecia, diarrhea, and failure to thrive, resembling acrodermatitis enteropathica (AE). Zinc supplements resolve symptoms without relapse after weaning. TNZD exhibits incomplete penetrance and variable expressivity, with some exclusively breastfed infants showing mild or no symptoms (PMID: 22733820). The condition typically follows an autosomal dominant inheritance pattern, though compound heterozygous and homozygous variants have been reported in mothers of early-onset TNZD infants (PMID: 23741301, 32278324). Eleven unique variants, including missense, nonsense, and frameshift mutations, documented in 13 unrelated mothers whose infants affected with TNZD across 10 publications (PMIDs: 17065149, 36967740, 22733820, 24194756, 24456035, 27304099, 28111782, 37082517, 23741301, 32278324) are included in this curation. The pathogenic mechanism involves loss-of-function through haploinsufficiency or dominant negative effects.
Experimental evidence further supports this gene-disease association. Knockout (KO) mice studies revealed higher cytoplasmic zinc levels in mammary gland cells compare to wildtype (WT) littermates, with altered zinc localization and accumulation (PMID: 25851903). These results are consistent with in vitro knockdown studies using siRNA in HC11 cells demonstrating cytoplasmic zinc trapping. In addition, ZnT2 null mice demonstrated reduction in milk zinc concentration and significantly lower litter survival (PMID: 25851903). Experimental studies on the TNZD associated variants including p.His54Arg, p.Gly87Arg, p.Gly280Arg, p.Thr312Met, p.Glu355Gln, p.Asp227Asn, p.Glu88Lys, p.Trp152Arg and p.Ser296Leu demonstrated various functional alterations including reduced zinc transport activity and secretion, zinc retention and mislocalization, decreased protein stability, and impaired dimerization in cell models (PMID: 17065149, 36967740, 22733820, 27137936, 23741301, 32278324). In addition, the c.838G>A p.Gly280Arg variant demonstrated aberrant splicing efficiency (PMID: 27304099).
In summary, there is definitive evidence to support the relationship between autosomal dominant loss of function variants in SLC30A2 and TNZD. This classification was approved by the ClinGen IEM GCEP on January 24, 2025 (SOP Version 11).
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