TNFRSF11A-Associated Dysosteosclerosis: A Report of the Second Case and Characterization of the Phenotypic Spectrum

Abstract

Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. DOS is genetically heterogeneous; however, only five cases with SLC29A3 mutations and a single case with a splice-site mutation of TNFRSF11A have been reported, and TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Thus, the causal genes of DOS and their genotype-phenotype associations remain unclear. In this study, we examined a Japanese patient with DOS and found a novel variant in TNFRSF11A. The homozygous variant was a G to T transversion at the first nucleotide of exon 9 (c.784G>T). Although the variant was predicted to cause a stop codon mutation (p.E262*), in silico evaluation of the exonic splicing elements followed by RT-PCR for the patient-derived cells showed that it caused aberrant splicing due to the change in the exonic splicing element and produced two types of aberrant transcripts: One caused a premature stop codon (p.E262Vfs*17) leading to nonsense mutation-mediated mRNA decay; the other produced a protein with interstitial deletion (p.E262_Q279del). The effects of the mutation on five splicing isoforms of TNFRSF11A were different from those in OP-AR7, but comparable with those in the first DOS with the TNFRSF11A mutation. Thus, we identified the second case of DOS caused by the TNFRSF11A splice-site mutation and confirmed the novel disease entity.

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

“…In contrast, the radiolucency in the enlarged lower metaphyseal parts was diffuse in the older cases (Case 1 and 2) (Guo et al, 2018;Xue et al, 2019). Moreover, although platyspondyly were found in all cases, concaved vertebrae at posterior thirds were present only in the older cases (Table 1) (Guo et al, 2018;Xue et al, 2019). In this study, our patient at age 19 months showed similarities to the previous young cases in both spinal and submetaphyseal changes (Figures 1C,E; Table 1).…”

“…Generally, the young cases (Case 3 and 4) had a clear radiolucent band in the submetaphyseal region of tubular bones, which was widely splayed and sclerotic (Xue et al, 2020;Xue et al, 2021a). In contrast, the radiolucency in the enlarged lower metaphyseal parts was diffuse in the older cases (Case 1 and 2) (Guo et al, 2018;Xue et al, 2019). Moreover, although platyspondyly were found in all cases, concaved vertebrae at posterior thirds were present only in the older cases (Table 1) (Guo et al, 2018;Xue et al, 2019).…”

“…It has been speculated that the clinical difference of DOS and OPTB7 may relate to the different effects of TNFRSF11A mutations in different TNFRSF11A isoform transcripts (Guo et al, 2018). The variants identified in the first three reported cases of TNFRSF11A-associated DOS cause NMD in some transcript isoforms, while simultaneously producing truncated or elongated RANK proteins in the remaining transcript isoforms according to the results of RT-PCR for the patient-derived cells and the exon trapping assay for cell lines (Guo et al, 2018;Xue et al, 2019;Xue et al, 2020). The functions of these truncated or elongated RANK proteins remain unclear.…”

“…To date, four DOS individuals with five different TNFRSF11A mutations (2 missense/nonsense, 2 splice-site, 1 deletion) have been reported (Guo et al, 2018;Xue et al, 2019;Xue et al, 2020;Xue et al, 2021a;Xue et al, 2021b). According to the previous hypothesis for genotype-phenotype relationship, aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to OPTB7 (Guo et al, 2018;Xue et al, 2019;Xue et al, 2020;Xue et al, 2021a). Herein, we present the fifth case of TNFRSF11A-associated DOS in a 19-month-old boy, in whom we identified a novel homozygous mutation in TNFRSF11A (c.19_31del;p.[Arg7CysfsTer172]).…”

From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R

“…DOS is mainly characterized by diffuse osteosclerosis, platyspondyly, and radiolucency of widened submetaphyseal portions of the tubular bones [20]. SLC29A3 and TNFRSF11A have been reported as the causal genes for DOS [21][22][23][24][25][26]. Pyle disease is caused by bi-allelic SFRP4 mutations and characterized by thin cortices, bone fragility and expanded trabecular metapyhyses [27].…”