TNFRSF11A – Dysosteosclerosis

Dysosteosclerosis (DOS) is a rare autosomal recessive sclerosing bone disorder characterized by irregular osteosclerosis of the long bones and platyspondyly (PMID:29568001). Although SLC29A3 mutations account for some cases, genetic heterogeneity was suggested by a Turkish patient in whom a novel TNFRSF11A splice-site mutation was identified, implicating TNFRSF11A as a second DOS gene (PMID:29568001).

The first TNFRSF11A-associated DOS case carried a homozygous splice-donor variant c.616+3A>G, shown by exon trapping to induce skipping of exon 6 and predicted frameshift with early termination in all transcript isoforms (PMID:29568001). A Japanese patient with homozygous c.784G>T (p.Glu262Ter) exhibited aberrant splicing producing p.Glu262ValfsTer17 and p.Glu262_Q279del isoforms, confirming loss-of-function via RT-PCR (PMID:31163101).

A third DOS case harbored compound heterozygous c.414_427+7del and c.1664del variants, generating both elongated and NMD-targeted RANK proteins across five isoforms (PMID:33037392). A fourth patient with homozygous c.19_31del (p.Arg7CysfsTer172) was predicted to undergo nonsense-mediated decay in all isoforms, reinforcing the role of truncated RANK in DOS (PMID:35812760).

The most recent adult case presented biallelic LoF alleles c.1093G>T (p.Glu365Ter) and c.1266_1268delinsCC (p.Leu422PhefsTer104) that escaped complete NMD, allowing residual RANK protein; patient-derived osteoclasts showed partial differentiation but severely impaired resorption consistent with clinical mild DOS (PMID:39906258).

Collectively, five unrelated probands with biallelic TNFRSF11A alleles exhibit DOS, all producing aberrant RANK proteins rather than null alleles seen in osteopetrosis. Functional studies—including exon trapping, RT-PCR and osteoclast resorption assays—demonstrate that these splice, nonsense and frameshift variants disrupt RANK signaling, underpinning the phenotype. Key Take-home: Biallelic aberrant-protein–producing TNFRSF11A variants cause dysosteosclerosis, enabling precise molecular diagnosis and informing potential targeted therapies.

References

• Journal of human genetics • 2018 • Dysosteosclerosis is also caused by TNFRSF11A mutation. PMID:29568001
• Journal of bone and mineral research • 2019 • TNFRSF11A-Associated Dysosteosclerosis: A Report of the Second Case and Characterization of the Phenotypic Spectrum. PMID:31163101
• Journal of human genetics • 2021 • The third case of TNFRSF11A-associated dysosteosclerosis with a mutation producing elongating proteins. PMID:33037392
• Frontiers in genetics • 2022 • A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis. PMID:35812760
• JBMR plus • 2025 • Paradoxical combination of osteosclerosis and osteopenia in an adult woman with biallelic TNFRSF11A loss-of-function variants escaping nonsense-mediated decay. PMID:39906258

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