Identification of a unique splice site variant in SLC39A4 in bovine hereditary zinc deficiency, lethal trait A46: An animal model of acrodermatitis enteropathica

Abstract

Lethal trait A46, also known as bovine hereditary zinc deficiency, Adema disease, and hereditary parakeratosis, is an autosomal recessive disorder first described in 1964, with a clinical presentation similar to that of acrodermatitis enteropathica (AE) in humans. The molecular basis of the defect has not been previously identified. Recently, the basic defect in AE was found to lie in SLC39A4. We report the characterization of the bovine ortholog of SLC39A4 and identification of a unique splice site variant within this gene in affected animals. The mutation leads to exon skipping, leaving the coding region in frame. The gene product is predicted to lack two critical motifs, which lie in adjacent transmembrane domains implicated in the formation of a pore responsible for the transport of zinc. While further functional studies are warranted, this unique variant is likely to be responsible for the impaired zinc absorption in this disease.

Analysis of the liver soluble proteome from bull terriers affected with inherited lethal acrodermatitis

“…The zinc deficiency symptoms are also consistent with those observed in zinc-responsive dermatosis in dogs [4,5], acrodermatitis enteropathica in humans [6][7][8], and lethal trait A46 in Black Pied Danish cattle [9,10]. These clinical symptoms include dermatitis, alopecia, anorexia, growth retardation, gastrointestinal dysfunction, defective T-lymphocyte function, and atrophy of the thymus and lymphoid tissues [1].…”

“…Parenteral treatment of the affected pups was unsuccessful as daily intravenous administration of 3 to 5 mg zinc sulfate in sterile saline caused vasculitis and intraperitoneal administration of the same solution resulted in granuloma formation [1]. Both acrodermatitis enteropathica in humans and lethal trait A 46 in cattle are caused by mutations in SLC39A4 [10,13] whereas the cause of LAD has not been identified.…”

Comparative Genomic Analysis of slc39a12/ZIP12: Insight into a Zinc Transporter Required for Vertebrate Nervous System Development

“…The SLC39 family, with similarity to iron transporter IRT1 [10], is present in Saccharomyces cerevisiae yeast [11], Arabidopsis plants [12], invertebrates [13], and vertebrates [14] including humans [15], [16]. The phenotypic similarities of zinc deficiency across different mammals due to impaired intestinal zinc transport caused by spontaneous or targeted mutations of slc39a4 (ZIP4) in humans [17], [18], mice [19], and cows [20] demonstrates how physiological functions for SLC39 members may be conserved across species.…”

Inherited Disorders in Danish Cattle

“…The molecular basis is a single nucleotide substitution in the gene SLC39A4 (313). In acrodermatitis enteropathica, a human analogue of bovine HZD (50,303), defects in the gene SLC39A4 have also been identified (166,300).…”