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Autosomal recessive osteopetrosis (ARO) is characterized by impaired osteoclast differentiation, leading to high bone density and marrow failure. In six unrelated individuals with osteoclast-poor ARO, biallelic mutations in TNFSF11 were identified, and affected bone specimens lacked TRAP-positive osteoclasts (PMID:17632511).
Genetic analysis revealed three distinct variants in TNFSF11: a frameshift c.828_829del (p.Val277fs), a splice-region deletion c.532+4_532+8del, and a missense c.596T>A (p.Met199Lys). All probands were homozygous or compound heterozygous for these alleles, consistent with autosomal recessive inheritance and demonstrating moderate genetic evidence (6 probands; AR segregation) (PMID:17632511).
Functional rescue experiments showed that exogenous recombinant RANKL restored osteoclast formation from patient monocytes in vitro, confirming loss of function of endogenous RANKL (PMID:17632511). A mouse model harboring the analogous Rankl G278R mutation replicates severe osteopetrosis with absent osteoclasts, and RANKL administration rescues bone resorption in vivo (PMID:22068587).
Structural studies of the human M199K variant revealed disrupted trimerization, impaired receptor binding, and reduced protein stability, elucidating the molecular mechanism of RANKL deficiency in ARO (PMID:32964459). These data provide strong functional evidence supporting haploinsufficiency of RANKL in AR osteopetrosis.
Integration of genetic and experimental findings substantiates a definitive mechanistic link between biallelic TNFSF11 variants and osteoclast-poor ARO. While genetic evidence is moderate by count, concordant in vitro rescue and in vivo models elevate the overall clinical validity to Strong.
Key Take-home: TNFSF11 sequencing should be included in AR osteopetrosis panels, and exogenous RANKL represents a potential targeted therapy for RANKL-deficient ARO.
Gene–Disease AssociationStrongSix probands across multiple families with AR inheritance and concordant functional rescue and animal model data Genetic EvidenceModerateSix unrelated probands with biallelic TNFSF11 variants (missense and loss-of-function); autosomal recessive segregation Functional EvidenceStrongExogenous RANKL restores osteoclastogenesis in patient cells (PMID:17632511); Rankl G278R mouse model recapitulates phenotype and is rescued by RANKL (PMID:22068587) |