Vitamin D-Binding Protein Deficiency and Homozygous Deletion of the GC Gene

Abstract

A 58-year-old woman with debilitating ankylosing spondylitis who was born to consanguineous parents was found to have an apparent severe vitamin D deficiency that did not respond to supplementation. Liquid chromatography-tandem mass spectrometry showed the absence of circulating vitamin D-binding protein, and chromosomal microarray confirmed a homozygous deletion of the group-specific component (GC) gene that encodes the protein. Congenital absence of vitamin D-binding protein resulted in normocalcemia and a relatively mild disruption of bone metabolism, in this case complicated by severe autoimmune disease. (Funded by the National Institutes of Health and the University of Washington.).

Figure 1.. Laboratory Data after Onset of Fragility Fractures.

Shown are clinical laboratory results for alkaline phosphatase, parathyroid hormone, serum calcium, and phosphate after the onset of fragility fractures. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for phosphate to millimoles per liter, multiply by 0.3229. Shaded areas show reference ranges: alkaline phosphatase, 30 to 115 U per liter and 30 to 145 U per liter; parathyroid hormone, 13 to 54 pg per milliliter and 7 to 37 pg per milliliter; calcium, 8.4 to 10.2 mg per deciliter; and phosphate, 2.5 to 4.6 mg per deciliter. The change in reference ranges for alkaline phosphatase and parathyroid hormone are the result of changes in instrumentation in the clinical laboratory during the time the measurements were obtained. Gray bars at the top of the figure provide a chronologic timeline of vitamin D supplementation. IM denotes intramuscular, and UVB ultraviolet B.

Figure 2.. SNP and FISH Analyses of GC Deletion.

Panel A shows results of single-nucleotide polymorphism (SNP) microarray for the patient. With the use of human genome assembly hg19, homozygous deletions of the group-specific component (GC) gene and part of the neuropeptide FF receptor 2 (NPFFR2) gene are shown on chromosome 4 at 4q13.3, spanning base pairs 72,581,969 to 72,720,986 and 72,839,592 to 72,984,080, respectively. The deletions, shown in purple and separated by an undeleted segment, are flanked by a small proximal 1.13-Mb region of homozygosity (71,449,909 to 72,575,787) and a large distal 66-Mb region of homozygosity (72,991,367 to 139,320,224), shown in yellow and denoted as ROH. The absence of allele peaks is consistent with homozygous deletions. The probes used for metaphase fluorescence in situ hybridization (FISH) are shown with the 4p16.3 control probe RP11–980G14 in green and the 4q13.3 GC probe G24P83578B9 in red. Panel B shows the results of FISH for the patient (left), a heterozygous sibling (middle), and a homozygous normal sibling (right).