A Deleterious Mutation in SAMD9 Causes Normophosphatemic Familial Tumoral Calcinosis

Topaz, Orit; Indelman, Margarita; Chefetz, Ilana; Geiger, Dan; Metzker, Aryeh; Altschuler, Yoram; Choder, Mordechai; Bercovich, Dani; Uitto, Jouni; Bergman, Reuven; Richard, Gabriele; Sprecher, Eli

doi:10.1086/508069

Cited by 124 publications

(108 citation statements)

References 24 publications

(20 reference statements)

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“…The exact function of SAMD9 is poorly understood, but it has antiviral activities against Japanese encephalitis virus (16), and its expression is induced by type I IFNs (17). SAMD9 also is a tumor suppressor, and mutations in the human SAMD9 gene are responsible for a rare life-threatening human disease, normophosphatemic familiar tumoral calcinosis (18).…”

Section: C7lmentioning

confidence: 99%

Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins

Meng

Krumm

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Human sterile alpha motif domain-containing 9 (SAMD9) protein is a host restriction factor for poxviruses, but it can be overcome by some poxvirus host-range proteins that share homology with vaccinia virus C7 protein. To understand the mechanism of action for this important family of host-range factors, we determined the crystal structures of C7 and myxoma virus M64, a C7 family member that is unable to antagonize SAMD9. Despite their different functions and only 23% sequence identity, the two proteins have very similar overall structures, displaying a previously unidentified fold comprised of a compact 12-stranded antiparallel β-sandwich wrapped in two short α helices. Extensive structure-guided mutagenesis of C7 identified three loops clustered on one edge of the β sandwich as critical for viral replication and binding with SAMD9. The loops are characterized with functionally important negatively charged, positively charged, and hydrophobic residues, respectively, together forming a unique "three-fingered molecular claw." The key residues of the claw are not conserved in two C7 family members that do not antagonize SAMD9 but are conserved in distantly related C7 family members from four poxvirus genera that infect diverse mammalian species. Indeed, we found that all in the latter group of proteins bind SAMD9. Taken together, our data indicate that diverse mammalian poxviruses use a conserved molecular claw in a C7-like protein to target SAMD9 and overcome host restriction.host-range factors | C7L | poxvirus | crystal structure | SAMD9

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Section: C7lmentioning

confidence: 99%

Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins

Meng

Krumm

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These recent studies show involvement of several genes. In the hyperphosphataemic familial tumoral calcinosis (FTC), mutations in GALTN3 and FGF23 have been observed [4,[10][11][12][13][14][15], whereas in the normophosphataemic FTC, the SAMD9 gene has been suggested to be involved [16]. In this patient, there was no family history or trauma to suggest or implicate an aetiological factor.…”

Section: Discussionmentioning

confidence: 71%

Large Tumoral Calcinosis in The Gluteal Region: A Case Report

Ym¹,

Ef²,

M³

et al. 2013

Ortop Traumatol Rehabil

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SUMMARYBackground. Tumoral calcinosis is a poorly understood phenomenon. It can be described as a syndrome of calcium deposits principally affecting the juxta-articular areas. It is a rare entity that has been poorly understood. Our aim is to highlight a special and unusual case of an 11-year-old with a large, relatively painless lump in her buttock.Clinical case. An 11-year-old girl of African descent presented to our Bone Tumour Unit after being referred by her local hospital. The girl presented with a large lump on the posterolateral aspect of the right buttock, measuring 15cm in diameter. Due to the delay in referral/diagnosis, tethering of the skin had progressed to necrosis, with a sinus discharging milky-white fluid. A MRI scan further characterised the lump as a densely calcified area within the gluteus maximus, extending to the subcutaneous tissue. The characteristic features of the calcified mass on the images led to the diagnosis of tumoral calcinosis. Laboratory test did not demonstrate any metabolic disturbances. Pathology reports further confirmed the diagnosis and the lump was successfully resected. There were no recurrences on follow-up.Conclusion. Several cases of tumoral calcinosis have been described in the literature; however, it remains a rare entity. Being aware of the possibility and having knowledge of tumoral calcinosis is paramount in preventing confusion and delay in diagnosis for patients and clinicians.

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“…Some studies attempted to classify them based on pathogenesis, 10 and others investigated the underlying genetic aberrations. 11 True TC (primary calcinosis) is an inherited disorder. The other soft tissue calcified mass lesions are essentially calcinosis secondary to various diseases such as chronic renal failure.…”

Section: Discussionmentioning

confidence: 99%