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Case Reports
. 2012 Nov 15;21(22):4904-9.
doi: 10.1093/hmg/dds326. Epub 2012 Aug 8.

Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis

Philippe M Campeau  1 , James T Lu, Gautam Sule, Ming-Ming Jiang, Yangjin Bae, Simran Madan, Wolfgang Högler, Nicholas J Shaw, Steven Mumm, Richard A Gibbs, Michael P Whyte, Brendan H Lee
Affiliations
Case Reports

Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis

Philippe M Campeau et al. Hum Mol Genet. .

Abstract

Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosis-lymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function.

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Figures

Figure 1.
Figure 1.
Radiographs of patients. Images from subject 1 at 33 months (and 22 months for the pelvis) are from Whyte et al. (1), and have been reproduced with authorization from the publisher. For subject 2, radiographs were taken at 4 years of age. Note the sclerosis at the skull base, periphery of the iliac wings and metaphyses, platyspondyly, and in the long bones cortical thickening at the diaphysis, diaphyseal enlargement with relative radiolucency and a fracture in subject 2.
Figure 2.
Figure 2.
Mutation details. Images from the exome alignments and the confirmation by Sanger sequencing for subjects 1 (A) and 2 (B). Location of mutations in the SLC29A3 gene (C) and protein (D). Asterisks denote known mutations in histiocytosis–lymphadenopathy plus syndrome [see mutation database at http://www.lovd.nl and reference (24) for more details]. (E) Amino acid conservation of the mutated residue across species.
Figure 3.
Figure 3.
(A) SLC29A3 expression in mouse osteoclasts. Nuclei stained by DAPI are in blue and SLC29A3 is in green. (B) Tartrate-resistant acid phosphatase (TRAP) staining of osteoclasts after 21 days of differentiation of human monocytes with RANKL and MCSF (105 cells/well in a 96-well plate). (C) Quantification of osteoclasts based on TRAP staining. Experiments were done in triplicate with an N of 2 per group (two affected and two unaffected); unaffected unrelated individuals were used as controls. (D–F) Osteoclastic function assessed by the ability of the in vitro-differentiated human osteoclasts to demineralize inorganic crystalline calcium phosphate coated on a polystyrene 96-well plate. Magnified images are shown in (D), the complete wells in (E) and a quantification of the demineralized surface in (F).
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