Abstract
Gamma-glutamyl carboxylase (GGCX) gene mutation causes GGCX syndrome (OMIM: 137167), which is characterized by pseudoxanthoma elasticum (PXE)-like symptoms and coagulation impairment. Here, we present a 55-year-old male with a novel homozygous deletion mutation, c.2,221delT, p.S741LfsX100, in the GGCX gene. Histopathological examination revealed calcium deposits in elastic fibers and vessel walls, and collagen accumulation in the mid-dermis. Studies of dermal fibroblasts from the patient (GGCX dermal fibroblasts) demonstrated that the mutated GGCX protein was larger, but its expression level and intracellular distribution were indistinguishable from those of the wild-type GGCX protein. Immunostaining and an enzyme-linked immunosorbent assay showed an increase in undercarboxylated matrix gamma-carboxyglutamic acid protein (ucMGP), a representative substrate of GGCX and a potent calcification inhibitor, indicating that mutated GGCX was enzymatically inactive. Under osteogenic conditions, calcium deposition was exclusively observed in GGCX dermal fibroblasts. Furthermore, GGCX dermal fibroblast cultures contained 23- and 7.7-fold more alkaline phosphatase (ALP)-positive cells than normal dermal fibroblast cultures (n = 3), without and with osteogenic induction, respectively. Expression and activity of ALP were higher in GGCX dermal fibroblasts than in normal dermal fibroblasts upon osteogenic induction. mRNA levels of other osteogenic markers were also higher in GGCX dermal fibroblasts than in normal dermal fibroblasts, which including bone morphogenetic protein 6, runt-related transcription factor 2, and periostin (POSTN) without osteogenic induction; and osterix, collagen type I alpha 2, and POSTN with osteogenic induction. Together, these data indicate that GGCX dermal fibroblasts trans-differentiate into the osteogenic lineage. This study proposes another mechanism underlying aberrant calcification in patients with GGCX syndrome.
Highlights
Gamma-glutamyl carboxylase (GGCX) activates a specific group of proteins (so-called gammacarboxyglutamic acid (Gla) proteins) by adding a carboxyl group to the gamma position of glutamine [1]
The clinical and pathological features that are similar in GGCX syndrome and pseudoxanthoma elasticum (PXE) are observed in other diseases, namely, generalized arterial calcification of infancy with ectonucleotide pyrophosphatase/phosphodiesterase 1 mutation (OMIM: 208000) [9], calcification of joints and arteries caused by deficiency of CD73 (OMIM: 212800), fibrodysplasia ossificans progressiva due to activin A receptor type I deficiency (OMIM: 135100) [10, 11], haemoglobinopathy with ß-globin mutation (OMIM: 613985) [12], and congenital erythropoietic porphyria with uroporphyrinogen III synthase mutation (OMIM: 606938) [13]
We reported a patient with a PXE-like disorder, GGCX syndrome, who had cutis laxa and sagging skin
Summary
Gamma-glutamyl carboxylase (GGCX) activates a specific group of proteins (so-called gammacarboxyglutamic acid (Gla) proteins) by adding a carboxyl group to the gamma position of glutamine [1]. Redundant skin and a bleeding tendency are observed in patients with GGCX syndrome. Vanakker et al [7] reported six patients with a severe pseudoxanthoma elasticum (PXE)-like skin appearance, relatively mild angioid streaks, and perturbed vitamin K-dependent coagulation factor activities, which drew attention to the similarity between the skin and eye phenotypes in GGCX syndrome and PXE (OMIM: 264800) [8]. The gamma position of certain glutamine residues of MGP is post-translationally carboxylated by GGCX [14]. Undercarboxylated, inactive, MGP in GGCX syndrome is thought to be involved in ectopic calcification; the precise process of calcification of elastic fibers is not known
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