TNFRSF11A-Associated Dysosteosclerosis: A Report of the Second Case and Characterization of the Phenotypic Spectrum.
J Bone Miner Res
; 34(10): 1873-1879, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31163101
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. © 2019 American Society for Bone and Mineral Research.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteosclerose
/
Éxons
/
Mutação Puntual
/
Códon de Terminação
/
Receptor Ativador de Fator Nuclear kappa-B
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article