Abstract
Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by platyspondyly and progressive osteosclerosis. DOS is genetically heterogeneous. Three causal genes, SLC29A3, CSF1R, and TNFRSF11A are reported. TNFRSF11A-associated DOS has been identified in two patients; however, TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Whole-exome sequencing in a patient with sclerosing bone disease identified novel compound heterozygous variants (c.414_427 + 7del, c.1664del) in TNFRSF11A. We examined the impact of the two variants on five splicing isoforms of TNFRSF11A by RT-PCR. We found that c.1664del resulted in elongated proteins (p.S555Cfs*121, etc.), while c.414_427 + 7del generated two aberrant splicing products (p.A139Wfs*19 and p.E132Dfs*19) that lead to nonsense mediated mRNA decay (NMD). In the previous two cases of TNFRSF11A-associated DOS, their mutations produced truncated TNFRSF11A protein isoforms. The mutations in all three cases thus contrast with TNFRSF11A mutations reported in OP-AR7, which does not generated truncated or elongated TNFRSF11A proteins. Thus, we identified the third case of TNFRSF11A-associated DOS and reinforced the genotype–phenotype correlation that aberrant protein-producing TNFRSF11A mutations cause DOS.
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Acknowledgements
We thank Mrs. Tomoko Otsuki for the technical support. This study is supported by grants from the Japan Society for the Promotion of Science (SI, No. 18H02932) and the Japan Agency For Medical Research and Development (SI, No. 20bm0804006h0104 and 20ek0109486h0001; NM, JP20ek0109486, JP20ek0109301, JP20ek0109348, and JP20kk0205012), CAMS Initiative Fund for Medical Sciences (ZW, 2016-I2M-3-003) and RIKEN Incentive Research Projects (ZW, 201801062228).
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Xue, JY., Wang, Z., Smithson, S.F. et al. The third case of TNFRSF11A-associated dysosteosclerosis with a mutation producing elongating proteins. J Hum Genet 66, 371–377 (2021). https://doi.org/10.1038/s10038-020-00831-8
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DOI: https://doi.org/10.1038/s10038-020-00831-8