Alternative titles; symbols
HGNC Approved Gene Symbol: GALNT3
Cytogenetic location: 2q24.3 Genomic coordinates (GRCh38) : 2:165,747,588-165,794,692 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q24.3 | Tumoral calcinosis, hyperphosphatemic, familial, 1 | 211900 | Autosomal recessive | 3 |
GALNT3 (EC 2.4.1.41) is one of several enzymes that catalyze the reaction UDP-GalNAc + polypeptide-(Ser/Thr)-OH to GalNAc-alpha-O-Ser/Thr-polypeptide + UDP, thereby initiating O-glycosylation of serine and threonine residues on an array of glycoproteins.
Bennett et al. (1996) used degenerate PCR to clone human GALNT3 using primers based on the sequences of GALNT1 (602273) and GALNT2 (602274). GALNT3 encodes a 633-amino acid protein which has a single membrane-spanning region and is highly homologous to GALNT1 and GALNT2. Northern blot analysis showed that GALNT3 is expressed as a 3.6-kb transcript, with highest levels in human pancreas and testis. Bennett et al. (1996) expressed the gene in insect Sf9 cells and showed that GALNT3 does have GalNAc-transferase activity, but with different substrate specificity than GALNT1 or GALNT2.
The mouse ortholog of GalNAc-T3 was cloned by Zara et al. (1996).
Bennett et al. (1998) found that the GALNT1, GALNT2, and GALNT3 genes contain 11, 16, and 10 exons, respectively. Several intron/exon boundaries are conserved within the 3 genes.
By FISH, Bennett et al. (1998) mapped the GALNT3 gene to human chromosome 2q24-q31.
Kato et al. (2006) identified GALNT3 as an enzyme that protects intact FGF23 (605380) from proteolytic processing. FGF23 is a phosphaturic protein whose secretion as an intact active form requires O-glycosylation by GALNT3. GALNT3 selectively directs O-glycosylation of FGF23 in a subtilisin-like proprotein convertase (SPC) recognition sequence motif at thr178, which blocks proteolytic processing of FGF23. The findings suggested a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation by GALNT3 and protease processing to produce intact FGF23. Mutations in GALNT3 result in a cleavage of intact FGF23 before secretion, leading to an accumulation of fragmented FGF23 and reduced intact active FGF23.
Autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) is a severe metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Topaz et al. (2004) assessed 12 individuals with familial tumoral calcinosis from 2 large kindreds of Druze and African American origin that had been extensively studied by Steinherz et al. (1985) and Slavin et al. (1993). All affected individuals reported recurrent painful, calcified subcutaneous masses of up to 1 kg, often resulting in secondary infection and incapacitating mutilation. Three individuals developed deep periarticular tumors, and 1 succumbed to the disorder. All affected individuals had hyperphosphatemia, but normal levels of calcium, parathyroid hormone (PTH; 168450), and 1,25-dihydroxyvitamin D3. Using linkage analysis in these 2 large kindreds, Topaz et al. (2004) mapped the gene underlying familial tumoral calcinosis to 2q24-q31. Sequence analysis of GALNT3, which lies in this region, identified biallelic deleterious mutations (601756.0001-601756.0003) in all affected individuals. The GALNT3 gene encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation, suggesting that defective posttranslational modification underlies the disorder.
Frishberg et al. (2005) identified homozygosity for a mutation in the GALNT3 gene (601756.0001) in 2 affected individuals from 2 Arab Moslem families with hyperostosis-hyperphosphatemia syndrome. The mutation had previously been reported in affected members of a Druze family with HFTC (Topaz et al., 2004), indicating that the 2 disorders are allelic. Haplotype analysis indicated a founder effect.
Specktor et al. (2006) identified a homozygous mutation in the GALNT3 gene (601756.0004) in an HFTC patient of northern European origin, suggesting that the disease may have a wider geographic distribution than previously thought.
Ichikawa et al. (2006) reported a 25-year-old Caucasian woman with eyelid calcifications and biochemical features of familial tumoral calcinosis. The patient carried 2 missense mutations in GALNT3 in compound heterozygosity, both substituting a positively charged lysine for an uncharged threonine (601756.0008, 601756.0009). Ichikawa et al. (2006) stated that all GALNT3 mutations leading to tumoral calcinosis reported to that time had been either nonsense or splice site mutations.
Ichikawa et al. (2010) reported 4 unrelated patients with hyperphosphatemia and recurrent calcified deposits in the bones or soft tissue associated with homozygous mutations in the GALNT3 gene (see, e.g. 601756.0011-601756.0012). One patient had a diagnosis of tumoral calcinosis, 1 hyperostosis-hyperphosphatemia syndrome, and 2 had diagnosis of both disorders. There were low levels of intact serum FGF23 (605380) and high levels of C-terminal FGF23 fragments in all 3 patients examined. Ichikawa et al. (2010) concluded that hyperostosis-hyperphosphatemia and tumoral calcinosis represent a continuous spectrum of the same disease caused by loss of GALNT3 function and low circulating intact FGF23.
In affected members of the Druze family with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) reported by Steinherz et al. (1985), Topaz et al. (2004) identified a homozygous G-to-A transition at position 1524+1 (from the ATG translation start site) of the GALNT3 gene, resulting in disruption of the intron 7 donor splice site consensus sequence.
Frishberg et al. (2005) identified homozygosity for the 1524+1G-A transition in 2 affected individuals from 2 Arab Moslem families with hyperostosis-hyperphosphatemia syndrome. Further population analysis estimated the frequency of the allele to be 0.70% in this population. Haplotype analysis confirmed a founder effect with the mutation arising approximately 88 to 200 years ago.
In affected members of an African American family with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) studied by Slavin et al. (1993), Topaz et al. (2004) found compound heterozygosity for 2 mutations in the GALNT3 gene: a nonsense mutation 484C-T, resulting in the amino acid substitution arg162-to-stop (R162X) in exon 1; and a splice site mutation, IVS7+5G-A (601756.0003).
See also 601756.0004 and Ichikawa et al. (2005).
For discussion of the splice site mutation in the GALNT3 gene that was found in compound heterozygous state in patients with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) by Topaz et al. (2004), see 601756.0002. This mutation, designated 1524+5G-A, alters the same splice donor site in intron 7 as 601756.0002.
In an African American patient with familial hyperphosphatemic tumoral calcinosis (HFTC1; 211900) belonging to a large affected kindred previously reported by McPhaul and Engel (1961) and Lyles et al. (1985), Ichikawa et al. (2005) identified compound heterozygosity for 2 mutations in the GALNT3 gene: an A-to-T transversion in intron 1 and R162X (601756.0002). The splice site mutation is predicted to lead to skipping of exon 2. An affected maternal great uncle was homozygous for the splice site mutation. Although the family had originally been described as showing autosomal dominant inheritance, the finding of biallelic mutations in 2 generations demonstrated that the family had pseudoautosomal dominant inheritance. The findings confirmed that tumoral calcinosis is in fact an autosomal recessive trait.
Laleye et al. (2008) identified homozygosity for the A-to-T transversion in intron 1 (516-2A-T) of the GALNT3 gene in 2 brothers with tumoral calcinosis from sub-Saharan Africa. The parents were consanguineous. RT-PCR analysis showed that the mutation resulted in the skipping of exon 2 and premature termination leading to a protein that lacks all domains encoded by exons 2 through 10. Both patients had a severe form of the disorder with dental enamel abnormalities and carbapatite deposits.
In a patient of northern European origin with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900), Specktor et al. (2006) identified a homozygous 1774C-T transition in exon 9 of the GALNT3 gene, resulting in a gln592-to-ter (Q592X) substitution predicted to result in a truncated protein lacking a significant portion of the carbohydrate-binding domain. The unaffected parents were heterozygous for the mutation, and the mutation was not found in 124 control chromosomes. The 32-year-old patient had severe joint disease and dental anomalies.
In an Italian man with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900), Barbieri et al. (2007) identified compound heterozygosity for 2 mutations in the GALNT3 gene: a 966T-G transversion in exon 4, resulting in tyr322-to-ter (Y322X) substitution and Q481X (601756.0007). Each unaffected parent and 2 unaffected sibs were heterozygous for 1 of the mutations.
In an Italian man with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900), Barbieri et al. (2007) identified compound heterozygosity for 2 mutations in the GALNT3 gene: a 1441C-T transition in exon 7, resulting in a gln481-to-ter (Q481X) substitution and Y322X (601756.0006).
In a patient with tumoral calcinosis (HFTC1; 211900) who presented with eyelid calcifications, Ichikawa et al. (2006) found compound heterozygosity for 2 missense mutations in the GALNT3 gene that substituted lysine for threonine. One was a C-to-A transversion at nucleotide 815 in exon 3 resulting in substitution of lysine for threonine at codon 272 (T272K); the other was a C-to-A transversion at nucleotide 1076 in exon 5 resulting in substitution of lysine for threonine at codon 359 (T359K; 601756.0009). Eyelid biopsy revealed superficial dermis calcifications. There was no history of metastatic calcifications, mineral homeostasis abnormalities, or renal dysfunction. Biochemistry revealed normal levels of calcium, creatinine, PTH (168450), and 25-hydroxyvitamin D, with elevated phosphorus, tubular maximum for phosphate reabsorption per deciliter of glomerular filtrate, and high normal 1,25-dihydroxyvitamin D levels. Elevated C-terminal FGF23 (605380) fragments with undetectable intact FGF23 suggested that the mutant enzyme lacked the ability to glycosylate FGF23 and that glycosylation by GALNT3 is necessary for secretion of functional full-length FGF23.
For discussion of the thr359-to-lys (T359K) mutation in the GALNT3 gene that was found in compound heterozygous state in a patient with tumoral calcinosis (HFTC1; 211900) by Ichikawa et al. (2006), see 601756.0008.
In a 5-year-old French boy with hyperostosis-hyperphosphatemia syndrome (HFTC1; 211900), Ichikawa et al. (2007) identified compound heterozygosity for 2 mutations in the GALNT3 gene: a 1-bp insertion (803_804insC) in exon 3, and a splice site mutation, IVS8+1G-A (601756.0011). The boy presented with painful cortical lesions in his leg, and radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar that in tumoral calcinosis. The patient's parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Ichikawa et al. (2007) suggested that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are different manifestations of the same disorder.
For discussion of the splice site mutation in the GALNT3 gene (IVS8+1G-A) that was found in compound heterozygous state in a patient with hyperostosis-hyperphosphatemia syndrome (HFTC1; 211900) by Ichikawa et al. (2007), see 601756.0010.
In a 5-year-old girl with hyperostosis-hyperphosphatemia syndrome/tumoral calcinosis (HFTC1; 211900), Ichikawa et al. (2010) identified a homozygous 1-bp deletion (677delC) in exon 3 of the GALNT3 gene, resulting in a frameshift and premature termination. The patient was born of first-degree cousins from Sri Lanka. She presented with painful left lower leg swelling which was found to be hyperostosis of the tibia with circumferential endosteal and periosteal bone formation; there was evidence of infection. In the following 2 years, she developed periarticular calcified lesions in the elbow, consistent with tumoral calcinosis. Laboratory studies showed increased serum phosphorus, normal calcium, and inappropriately normal 1,25-(OH)2D. There were also low levels of intact FGF23 (605380) and increased C-terminal FGF23 fragments, consistent with tumoral calcinosis. Ichikawa et al. (2010) concluded that hyperostosis-hyperphosphatemia syndrome and tumoral calcinosis represent a continuous spectrum of the same disease caused by loss of GALNT3 function and low circulating intact FGF23.
In a Greek woman with hyperphosphatemic tumoral calcinosis/ hyperostosis-hyperphosphatemia (HFTC1; 211900), Ichikawa et al. (2010) identified a homozygous 1720T-G transversion in exon 10 of the GALNT3 gene, resulting in a cys574-to-gly (C574G) substitution. The patient presented at age 8 years with a tibial lesion involving the cortical and trabecular bones with subperiosteal ossification. At age 14, she had subcutaneous calcified lesions of the upper thigh and left hand. Laboratory studies at age 15-16 showed hyperphosphatemia, inappropriately increased/normal 1,24-(OH)2D, and normal serum calcium. There were also low/normal levels of intact FGF23 (605380) and increased C-terminal FGF23 fragments, consistent with tumoral calcinosis. Ichikawa et al. (2010) concluded that hyperostosis-hyperphosphatemia syndrome and tumoral calcinosis represent a continuous spectrum of the same disease caused by loss of GALNT3 function and low circulating intact FGF23.
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