TNFRSF11A – Osteopetrosis, Autosomal Recessive 7

TNFRSF11A (RANK) is inherited in an autosomal recessive manner and null alleles are hypothesized to underlie osteopetrosis, autosomal recessive 7 (OPTB7). To date, only one homozygous frameshift variant, c.19_31del (p.Arg7CysfsTer172), has been observed in a patient, but surprisingly resulted in dysosteosclerosis rather than classical osteopetrosis, suggesting limited direct genetic evidence for OPTB7 (PMID:35812760). No confirmed probands with biallelic null TNFRSF11A presenting with OPTB7 have been reported, and there is no segregation data supporting this specific phenotype.

Functional studies demonstrate that truncating mutations abolishing the pre-ligand assembly domain (PLAD) of RANK impair ligand-independent oligomerisation and downstream NF-κB activation, leading to osteoclast‐poor osteopetrosis in vitro and in mouse models (G280X, W434X) (PMID:24859969); homozygous insertion mutations similarly yield osteopetrosis in mice (PMID:33724536). These data support a pathogenic mechanism of loss of function but phenotypic specificity for OPTB7 remains unclear. Additional clinically ascertained cases with AR osteopetrosis are needed to establish TNFRSF11A as a definitive gene for OPTB7.

Key Take-home: TNFRSF11A loss-of-function variants impair osteoclastogenesis, but current human data provide limited support for a distinct OPTB7 phenotype.

References

• Frontiers in Genetics • 2022 • A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis. PMID:35812760
• Journal of Molecular Endocrinology • 2014 • RANK receptor oligomerisation in the regulation of NFκB signalling PMID:24859969
• Journal of Bone and Mineral Research • 2021 • Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice. PMID:33724536

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