Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.We assessed 12 individuals with FTC from two large kindreds of Druze and African-American origin (Fig. 1a) that have been extensively described 1,2 . All affected individuals reported recurrent painful, calcified subcutaneous masses of up to 1 kg (Fig. 1b), often resulting in secondary infection and incapacitating mutilation. Three individuals developed deep periarticular tumors (Fig. 1b), and one succumbed to the disease. All affected individuals had hyperphosphatemia (family 1, 6.2-8.5 mg dl -1 ; family 2, 5.2-6.6 mg dl -1 ) but normal levels of calcium, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3.With informed consent of all participants, we obtained DNA samples and carried out a genome-wide scan using 362 microsatellite markers (Research Genetics) in family 1. Consanguinity in this kindred allowed us to apply homozygosity mapping to identify in all affected individuals a 15-Mb segment identical by descent, flanked by D2S142 and D2S2284/D2S2177 on 2q24-q31 (Fig. 1). We obtained a maximum multipoint lod score of 6.7 (HOMOZ 3 ). Multipoint linkage analysis in family 2 using seven markers in this critical region further reduced the interval to 3 Mb flanked by D2S111 and D2S1776 (Fig. 1) and yielded a maximum multipoint lod score of 3.4 (GeneHunter 4 ).Using Mapviewer, we identified 11 genes in the 3-Mb region associated with FTC. Of these, B3GALT1, SCN7A, SCN9A, SCN1A and STK39 have roles in neural or neuroendocrine tissues; the functions of TAIP-2, CMYA3, FLJ11457, LOC90643 and LASS6 are mostly unknown. The last positional candidate gene, GALNT3, encodes the UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (ppGaNTase-T3; ref. 5). ppGaNTase-T3 belongs to a large family of Golgi-associated biosynthetic enzymes that transfer GalNac from the sugar donor UDP-GalNac to serine and threonine residues and are thereby responsible for initiating O-glycan synthesis, a prevalent form of post-translational modification 6 . RT-PCR analysis showed strong expression of GALNT3 in the skin and kidneys, two tissues of functional relevance to the pathogenesis of FTC 1,2 (Fig. 2a). Using balanced primer pairs, we screened PCR amplicons of all ten coding exons and conserved splice sites of GALNT3 for pathogenic mutations in the genomic DNA of affected individuals (primer pairs and PCR conditions are available on request). Members of the Druze family carried a homozygous G→A transition at position 1524+1 (from the ATG ...

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Gap junction communication in the human corneal epithelium is mediated by Cx26, -30, -31.1, and -43. Poorly differentiated PCECs are uncoupled, and Ca(2+) induced differentiation is associated with an upregulation of connexin expression and intercellular communication. The transfection experiments suggest that KIDS Cx26(D50N) impairs intracellular formation and transport of connexons formed by Cx26 and -30, consistent with a dominant negative effect.

We report on two young adults with KID syndrome and follicular hyperkeratosis, hidradenitis suppurativa of the groin, progressive development of proliferative pilar cysts and dissecting cellulitis of the scalp, who developed metastatic malignant pilar tumors. Based on our findings, we believe that cancer surveillance in patients with KID syndrome should include screening for pilar tumors and their early removal to avoid development of malignant proliferating pilar tumors with poor prognosis.

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