Heritable disorders that feature high bone mass are rare. The etiology is typically a mutation(s) within a gene that importantly regulates the differentiation and function of osteoblasts (OBs) positively, or osteoclasts (OCs) negatively. Nevertheless, the genetic basis is unknown for approximately one-fifth of such disorders. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. Deletion of the p50 and p52 subunits causes osteopetrosis (OPT) in mice. Mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported in humans. We describe a neonate who died unexpectedly and was found at postmortem to have high bone mass documented radiographically and by skeletal histopathology. Radiographic changes resembled malignant OPT, but histopathological investigation instead indicated accelerated bone formation with morphologically normal OCs and intact bone resorption, thus excluding a form of OPT. Mutation analyses revealed no pathogenic mutation in eight genes associated with OPT. Subsequently, trio-based whole exome sequencing involved exome capture using SureSelect Human All Exon V5 (Agilent Technologies) followed by sequencing on the Illumina HiSDefault 2000 platform. A change in exon 11 of RELA encoding Rela/p65 was validated by bi-directional Sanger sequencing. This revealed that the neonate carried a de novo, heterozygous, missense mutation (p.Asp512Ser) in RELA. Thus far, four additional unrelated patients with unexplained high bone mass have not shown a RELA mutation. Ours is the first report of a RELA mutation in humans. The defect is associated with neonatal osteosclerosis apparently from increased in utero OB function rather than decreased OC action. This finding demonstrates the importance for skeletal homeostasis of the Rela/p65 subunit within the NF-κB pathway, and represents a new genetic cause of high bone mass.
Disclosure: Supported by Shriners Hospitals for Children, The Hypophosphatasia Research Fund at The Barnes-Jewish Hospital Foundation, and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number DK067145.