Mendelian Disorders of RANKL/OPG/RANK Signaling

Whyte, Michael P.

doi:10.1016/b978-0-12-387829-8.00020-2

Cited by 23 publications

(61 citation statements)

References 55 publications

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“…Most JPD is caused by AR loss-of-function defects within TNFRSF11B , (13) but otherwise the etiology is unknown. (4) Instead, she carries a unique heterozygous 15-bp insertional tandem duplication within TNFRSF11A (RANK) that the related “exonic” disorders FEO, PDB2, ESH, and PEBD identify as gain-of-function. (4, 10) Our findings reveal for JPD a second genetic basis (i.e.…”

Section: V) Discussionmentioning

confidence: 99%

“…(4) Instead, she carries a unique heterozygous 15-bp insertional tandem duplication within TNFRSF11A (RANK) that the related “exonic” disorders FEO, PDB2, ESH, and PEBD identify as gain-of-function. (4, 10) Our findings reveal for JPD a second genetic basis (i.e. ; “JPD1” and now “JPD2”) and the potential for AD inheritance, and for the disorders of constitutive RANK activation a broader phenotype.…”

Section: V) Discussionmentioning

confidence: 99%

“…(2) Then, their importance for humans became certain when mutations within TNFSF11 (RANKL), TNFRSF11A (RANK), and TNFRSF11B (OPG) explained disorders that resemble Paget’s disease of bone (PDB1: OMIM #167250) (3) with enhanced osteoclastogenesis and accelerated skeletal remodeling, or are osteopetroses that feature diminished osteoclastogenesis and failure of bone resorption. (4) …”

Section: Ii) Introductionmentioning

confidence: 99%

“…(4) In 2002, Whyte et al (11) and Cundy et al (12) discovered that this autosomal recessive (AR) disorder can be caused by loss-of-function mutations within TNFRSF11B that encodes OPG. Typically, unique homozygous TNFRSF11B mutations represent a “founder” in different geographical regions.…”

Section: Ii) Introductionmentioning

confidence: 99%

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Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

Whyte

Tau

McAlister

et al. 2014

Bone

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Mendelian disorders of RANKL/OPG/RANK signaling feature the extremes of aberrant osteoclastogenesis and cause either osteopetrosis or rapid turnover skeletal disease. The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK. Juvenile Paget’s disease (JPD), an autosomal recessive disorder, manifests extremely fast skeletal remodeling, and is usually caused by loss-of-function mutations within TNFRSF11B that encodes OPG. These disorders are ultra-rare. A 13-year-old Bolivian girl was referred at age 3 years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2 years involved missing ossicles and eroded cochleas. Teeth often had absorbed roots, broke, and were lost. Radiographs had revealed acquired tubular bone widening, cortical thickening, and coarse trabeculation. Biochemical markers indicated rapid skeletal turnover. Histopathology showed accelerated remodeling with abundant osteoclasts. JPD was diagnosed. Immobilization from a femur fracture caused severe hypercalcemia that responded rapidly to pamidronate treatment followed by bone turnover marker and radiographic improvement. No TNFRSF11B mutation was found. Instead, a unique heterozygous 15-bp insertional tandem duplication (87dup15) within exon 1 of TNFRSF11A predicted the same pentapeptide extension of RANK that causes expansile skeletal hyperphosphatasia (84dup15). Single nucleotide polymorphisms in TNFRSF11A and TNFRSF11B possibly impacted her phenotype. Our findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

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Section: V) Discussionmentioning

confidence: 99%

Section: V) Discussionmentioning

confidence: 99%

Section: Ii) Introductionmentioning

confidence: 99%

Section: Ii) Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

Whyte

Tau

McAlister

et al. 2014

Bone

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“…A single base pair insertion of M-CSF receptor gene Csfm in mice is the cause of the recessive mutation osteopetrosis (op) [3]. In human, an activating mutation of rank gene and a deactivating mutation of opg (encoded for osteoprotegerin, OPG) gene cause familiar expansile osteolysis and Paget's disease of bones [4]. OPG is a decoy receptor for RANKL that is also secreted by osteoblasts and inhibits the binding of RANKL to RANK, blocking the differentiation of osteoclasts [5].…”

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confidence: 99%

NFAT Signaling and Bone Homeostasis

Chen¹,

Pan²

2013

J Hematol Thrombo Diseases

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Bone homeostasis is a function of the constant balancing acts between osteoclasts and osteoblasts, regulated by numerous factors in cellular and molecular levels. Calcineurin-NFAT pathway plays critical roles in bone homeostasis by regulating many aspects of bone development and remodeling. NFATc1 is the master transcription factor of osteoclasts, acting downstream of RANKL (receptor activator of nuclear factor-κB ligand) to control osteoclastogenesis. NFATc1 also plays important role in osteoblastogenesis, its increased nuclear occupancy in osteoblasts causes osteopetrosis by regulating chemokine and Wnt pathways. Targeting NFAT pathway may provide therapeutic avenues for treating bony disorders.

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Multicentric carpotarsal osteolysis syndrome is caused by only a few domain‐specific mutations in MAFB, a negative regulator of RANKL‐induced osteoclastogenesis

Mumm

Huskey

Duan

et al. 2014

American J of Med Genetics Pt A

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Multicentric carpotarsal osteolysis syndrome (MCTO), an autosomal dominant disorder that often presents sporadically, features carpal-tarsal lysis frequently followed by nephropathy and renal failure. In 2012, mutations in the single-exon gene MAFB were reported in 13 probands with MCTO. MAFB is a negative regulator of RANKL-mediated osteoclastogenesis. We studied 9 MCTO patients (7 sporadic patients and one affected mother and son) for MAFB mutation. We PCR-amplified and selectively sequenced the MAFB region that contains the transactivation domain in this 323 amino acid protein, where mutations were previously reported for MCTO. We found 5 different heterozygous missense defects among 8 probands: c.176C>T, p.Pro59Leu; c.185C>T, p.Thr62Ile; c.206C>T, p.Ser69Leu (4 had this defect); c.209C>T, p.Ser70Leu; and c.211C>T, p.Pro71Ser. All 5 mutations are within a 13 amino acid stretch of the transactivation domain. Four were identical to the previously reported mutations. Our unique mutation (c.185C>T, p.Thr62Ile) involved the same domain. DNA available from 7 parents of the 7 sporadic patients did not show their child’s MAFB mutation. The affected mother and son had an identical defect. Hence, the mutations for 7/8 probands were suspected to have arisen spontaneously as there was no history of features of MCTO in either parent. Penetrance of MCTO seemed complete. Lack of nonsense or other truncating mutations suggested a dominant-negative pathogenesis. Our findings indicate that only a few transactivation domain-specific mutations within MAFB cause MCTO.

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Mendelian Disorders of RANKL/OPG/RANK Signaling

Cited by 23 publications

References 55 publications

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

NFAT Signaling and Bone Homeostasis

Multicentric carpotarsal osteolysis syndrome is caused by only a few domain‐specific mutations in MAFB, a negative regulator of RANKL‐induced osteoclastogenesis

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