Specktor P, Cooper JG, Indelman M, Sprecher EHyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred. J Hum Genet 51:487-490

Department of Dermatology, Laboratory of Molecular Dermatology, Rambam Medical Center, POB 9602, 31096, Haifa, Israel.
Journal of Human Genetics (Impact Factor: 2.46). 02/2006; 51(5):487-90. DOI: 10.1007/s10038-006-0377-6
Source: PubMed


Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein. All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and African-American populations.

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    • "Initially genetic linkage-analysis of affected individuals identified bi-allelic deleterious mutations in GALNT3 leading to loss of the GalNAc-T3 enzyme [38]. Later multiple studies reported findings of biallelic inactivated GALNT3 in patients suffering from FTC and HHS [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68]. Furthermore locus heterogeneity exists in FTC as inactivating mutations in FGF23 and the FGF receptor-modulating gene, KLOTHO, both cause FTC, pointing to a common biological pathway [69] [70] [71]. "
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    ABSTRACT: Posttranslational modifications (PTMs) greatly expand the function and regulation of proteins, and glycosylation is the most abundant and diverse PTM. Of the many different types of protein glycosylation, one is quite unique; GalNAc-type (or mucin-type) O-glycosylation, where biosynthesis is initiated in the Golgi by up to twenty distinct UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). These GalNAc-Ts are differentially expressed in cells and have different (although partly overlapping) substrate specificities, which provide for both unique functions and considerable redundancy. Recently we have begun to uncover human diseases associated with deficiencies in GalNAc-T genes (GALNTs). Thus deficiencies in individual GALNTs produce cell and protein specific effects and subtle distinct phenotypes such as hyperphosphatemia with hyperostosis (GALNT3) and dysregulated lipid metabolism (GALNT2). These phenotypes appear to be caused by deficient site-specific O-glycosylation that co-regulates proprotein convertase (PC) processing of FGF23 and ANGPTL3, respectively. Here we summarize recent progress in uncovering the interplay between human O-glycosylation and protease regulated processing and describes other important functions of site-specific O-glycosylation in health and disease. Site-specific O-glycosylation modifies pro-protein processing and other proteolytic events such as ADAM processing and thus emerges as an important co-regulator of limited proteolytic processing events. Our appreciation of this function may have been hampered by our sparse knowledge of the O-glycoproteome and in particular sites of O-glycosylation. New strategies for identification of O-glycoproteins have emerged and recently the concept of SimpleCells, i.e. human cell lines made deficient in O-glycan extension by zinc finger nuclease gene targeting, was introduced for broad O-glycoproteome analysis.
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    • "This processing can be blocked by selective O-glycosylation of the cleavage site by GALNT3 (85). Indeed, mutations of GALNT3 or serine 71/glycine (S71G) and serine 129/phenylalanine (S129F) mutations of FGF23 at additional glycosylation sites result in hyperphosphatemic familial tumoral calcinosis (HFTC) (11, 189, 204). The defective O-glycosylation observed in HFTC is associated with hyperphosphatemia and massive ectopic calcifications and leads to low intact FGF23 levels with marked increase of processed COOH-terminal fragments in the circulation. "
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    ABSTRACT: Calcium (Ca(2+)) and phosphate (PO(4)(3-)) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca(2+) levels by increasing Ca(2+) reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] production by the kidney, enhancing Ca(2+) and PO(4)(3-) intestinal absorption and increasing Ca(2+) and PO(4)(3-) efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)(2)D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)(2)D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO(4)(3-) handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.
    Full-text · Article · Jan 2012 · Physiological Reviews
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    • "More than 10 mutations have so far been reported in GALNT3 (Topaz et al., 2004; Ichikawa et al., 2005, 2006; Campagnoli et al., 2006; Garringer et al., 2006, 2007; Specktor et al., 2006; Barbieri et al., 2007; Dumitrescu et al., 2009; Laleye et al., 2008); all of these are predicted or have been found (Topaz et al., 2005) to result in loss of function of ppGalNacT3. Deleterious alterations in GALNT3 were also found to underlie at least one additional autosomal recessive syndrome, hyperostosis–hyperphosphatemia syndrome (MIM610233), which, as HFTC, is also associated with elevated levels of serum phosphate (Melhem et al., 1970; Altman and Pomerance, 1971; Mikati et al., 1981). "
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    ABSTRACT: Familial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases.
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