Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3

Abstract

Acrodermatitis enteropathica (AE) is a rare autosomal recessive pediatric disease characterized by dermatitis, diarrhea, alopecia, and growth failure. The disease results from insufficient uptake of zinc by the intestine and can be fatal unless the diet is supplemented with zinc. To map the gene responsible for AE, a genomewide screen was performed on 17 individuals, including 4 affected individuals, in a consanguineous Jordanian family. Three markers-D8S373, D10S212, and D6S1021-had a pattern consistent with tight linkage to a recessive disease: one allele in the affected sibs and multiple alleles in unaffected sibs and parents. Two-point parametric linkage analysis using FASTLINK identified one region, D8S373, with a maximum LOD score >1.5 (1.94 at D8S373: recombination fraction.001). Twelve additional markers flanking D8S373 were used to genotype the extended family, to fine-map the AE gene. All five affected individuals-including one who was not genotyped in the genomewide screen-were found to be homozygous for a common haplotype, spanning approximately 3.5 cM, defined by markers D8S1713 and D8S2334 on chromosomal region 8q24.3. To support these mapping data, seven consanguineous Egyptian families with eight patients with AE were genotyped using these markers, and six patients from five families were found to be homozygous in this region. Multipoint analysis with all consanguineous families, by Mapmaker/Homoz, resulted in a maximum LOD score of 3.89 between D8S1713 and D8S373. Sliding three-point analysis resulted in a maximum LOD score of 5.16 between markers D8S1727 and D8S1744.

Figure 1

Jordanian pedigree with AE. A, Patient (corresponding to the filter card in the pedigree) showing perianal skin lesions. The perioral region shows an exudative and crusted area on an erythematous base, with irregular outline. The scalp hair is sparse, diarrhea is present, and the elbows and knees show scaly erythematous and thickened skin (psoriasiform). Periungal erythema and slightly swollen folds are present, and the nape of the neck shows slight psoriasiform rash. B, Haplotypes of the Jordanian pedigree, for 13 microsatellite markers at 8q24.3. Haplotypes were constructed by inspection, and those that are homozygous in affected individuals are boxed.

Figure 2

Pedigrees of seven consanguineous Egyptian families with genotypes of 10 microsatellite markers at 8q24.3. For compactness, only the relevant portions of the pedigrees are shown. Haplotypes/markers that are homozygous in affected individuals are boxed.

Figure 3

Graph of three-point and multipoint LOD scores, against distance (in cM), at 8q24.3. For sliding three-point analysis, the maximum LOD score is 5.16. Homozygosity mapping gives a maximum LOD score of 3.89. Mapmaker/Homoz was used for homozygosity mapping.