Mikä geenitausta on hyperfosfatemisen tumoraalin kalsinoosin takana?

1.  hakusana Hyperphosphataemic tumoral calcinosis
2. Ilmenee geeni GLNT3 mutaatioita   Katon lopuksi GALNT3 geenin ihmisellä

2007

J Clin Endocrinol Metab. 2006 Nov;91(11):4472-5. Epub 2006 Aug 29.

Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene.

Ichikawa S¹, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, Shaker JL, Econs MJ.

2009

Endocrinology. 2009 Jun;150(6):2543-50. doi: 10.1210/en.2008-0877. Epub 2009 Feb 12.

Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression.

Ichikawa S¹, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ.

 2011

https://www.ncbi.nlm.nih.gov/pubmed/22009723/

Endocrinology. 2011 Dec;152(12):4504-13. doi: 10.1210/en.2011-1137. Epub 2011 Oct 18.

Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis.

Ichikawa S¹, Austin AM, Gray AK, Allen MR, Econs MJ.

 

2014 

 

https://www.ncbi.nlm.nih.gov/pubmed/25249269 

BMC Genet. 2014 Sep 24;15:98. doi: 10.1186/s12863-014-0098-3.

Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.

Rafaelsen S, Johansson S, Ræder H, Bjerknes R.

 

 2015 

Curr Osteoporos Rep. 2015 Apr;13(2):78-87. doi: 10.1007/s11914-015-0254-3.

Hyperphosphatemic familial tumoral calcinosis: genetic models of deficient FGF23 action.

Folsom LJ¹, Imel EA.

 

 2016

 https://www.ncbi.nlm.nih.gov/pubmed/27164190

J Bone Miner Res. 2016 Oct;31(10):1845-1854. doi: 10.1002/jbmr.2870. Epub 2016 Sep 20.

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.

Ramnitz MS¹, Gourh P², Goldbach-Mansky R², Wodajo F³, Ichikawa S⁴, Econs MJ^4,5, White KE⁵, Molinolo A¹, Chen MY⁶, Heller T⁷, Del Rivero J⁸, Seo-Mayer P⁹, Arabshahi B¹⁰, Jackson MB¹¹, Hatab S¹², McCarthy E¹³, Guthrie LC¹, Brillante BA¹, Gafni RI¹, Collins MT¹⁴.

 

 

Oxfordilainen dieettiohje fosfaattia (Pi) rajoittavasta dieetissä

https://www.ouh.nhs.uk/oku/patient-advice/documents/phosphate-diet.pdf
Tämä oxfordilainen  artikkeli pyrkii  epäorgaanisen fosfaatin alentamiseen eikä  hienosäätele  erikseen insoitolifosfaatin suhteen, ainoastaan  suosittelee  siihen suuntaan  viitaten  kasviperäiseen  ravintoa, jossa inositolifosfaattia voi onnistua saamaan.

 https://www.ouh.nhs.uk/oku/patient-advice/documents/phosphate-diet.pdf
On itseasiassa  paradigman muutosta jos  inositolifosfaatti (IP6 ja IP3)  aletaan ottaa  fosfaattiaineenvaihdunnan terapiassa huomioon. 

Hyperfosfateminen tumoröösi kalsinoosi (Lancet uutinen)

 Lancet  Numero 10167, Vol 393. Jan 12, 2019 
Lehti kuvaa  havinaisen potilastapauksen.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33045-9/fulltext?rss=yes
18-vuotiaalla nuorella miehellä 1 vuoden kestäneiden vasemman  lonkan alueen vaivan selvittelyssä  lopulta  hyperfosfateminen tuumorin muodostanut  kalsinoosi. 
Mitään traumaa ei ollut anamneesissa ei myöskään mitään autoimmuunisiin häiriöihin viitaavaa.  Tuumorimassa isontrokanterin seudussa oli lisäksi paloiden aristavaa ja rajoitti nivelen liikuntaa, lonkan  rotaatiota ja abduktiota.  Aiemmassa omassa ja perheanamneesissa ei ollut  syitä selvittävää.  Tgasoröntgentutkimus ja tietokonetomografia selvittivä  molemmin puolisen, bilateraalisen, vierasvarjon, joka oli  periartikulaarinen, lohkoinen, kalkkiutunut pehmytosamassa - vasemmalla  tämä röäntgenologinen löytö oli selvempi kuin oikella. 
Nyt selvitettiin seerumia:  S-urfea, kreatiniini, virtsahappo, kokonaiskalsium, alkaalinen fosfaatti ja PTH( paratyreoideahormoni) - nämä kaikki olvat normaaleita.
 Sensijaan  seeurin epäorgaaninen fosfaatti (Pi) oli koholla: 2- 19 mmol/L. ( Normaalialue on 0.81- 1.45 mmol/l).
 Munuaisen tubulaarinen  maksimaalinen  fosfaatin reabsorptiotahti korjattuna glomerulaarisen  filtraation suhteen  oli myös koholla  2-16 mmol/L ( normaalialue on 1.07- 1.89 mmol/L)  ja tämä  viittasi munuaisen kohonneeseen tubulaariseen fosfaatin takaisin absorptioon
Ottaen huomioon potilaan iän ja  lonkkaseudun bilateraaliset , periartikulaarisessa pehmeässä  kudoksessa sijaitsevat, kalkkiutuneet massat , fosfaatin reabsorptioon liittyneen hyperfosfatemian  ja sekundäärisistä  tai muista syistä   ektooppisiin kalkkiutumiin johtavien seikkojen puuttumisen potilaan diagnoosiksi asetettiin  hyperfosfateminen tumoraali kalsinoosi. 
Tehtiin oireenmukainen  vasemman puolisen massan kirurginen  poisto. Operaaation aikana havaittiin  kystistä massaa, jonka sisällä oli liituista  valkoista materiaalia . Histologinen tutkimus osoitti amorfista kalkkiutunutta jyväistä materiaalia, jota ympäröi histiosyytti- ja jättisolureaktio, mikä vahvisti diagnoosin. 
Operaation jälkeen  tehtiin yrityksiä alentaa veren fosfaattipitoisuutta käyttäen kombinoidusti  fosfaattiredusoitua dieettiä  ja  alle 800 mg tablettia   kalsiumitonta   fosfaatin sitojaa  sevelamerihydrokloridia, joka sitää suolistossa fosfaattia, sekä  p.o. asetatsolamidia , joka indusoi fosfaturiaa.

• Postoperatively, attempts were made to lower the patient's blood phosphate concentration using a combination of a phosphate-restricted diet with less than 800 mg/day tablets of the non-calcium-based phosphate binder, sevelamer hydrochloride—which binds phosphate in the intestine, and oral acetazolamide to induce phosphaturia.

• An 18-year-old man presented to our department with a 1-year history of pain in the region of his left hip and difficulty in squatting. He reported no history of any local trauma. There was no history suggestive of an autoimmune disorder. Clinical examination found a tender, hard mass in the left greater trochanteric region with painful, restricted rotation and abduction movements of the hip. Both his medical history and family history were unremarkable. Plain x-ray and CT scans of the pelvis ( figure) showed bilateral—left greater than the right—and periarticular, lobulated, calcific, soft tissue masses. Serum urea, creatinine, uric acid, total calcium, alkaline phosphate, and parathyroid hormone concentrations were normal. However, serum inorganic phosphorus was elevated at 2·10 mmol/L (normal range 0·81–1·45 mmol/L). The ratio of the renal tubular maximum reabsorption rate of phosphate to corrected glomerular filtration rate was also elevated at 2·16 mmol/L (normal range 1·07–1·89 mmol/L), suggestive of increased renal tubular phosphate reabsorption.

•  Considering the patient's age, presence of bilateral, and periarticular soft tissue, calcific masses about the hip, hyperphosphataemia with increased tubular phosphate reabsorption, and the absence of indications that the ectopic calcification was secondary to any other causes, the patient was diagnosed with hyperphosphataemic tumoral calcinosis. 

• The symptomatic, left-sided mass was surgically excised: during the operation it appeared as a cystic mass containing chalky white material. Histological examination showed amorphous and granular calcified material surrounded by histiocytic and giant cell reaction—confirming the diagnosis. Postoperatively, attempts were made to lower the patient's blood phosphate concentration using a combination of a phosphate-restricted diet with less than 800 mg/day tablets of the non-calcium-based phosphate binder, sevelamer hydrochloride—which binds phosphate in the intestine, and oral acetazolamide to induce phosphaturia.

Human NUDIX genes

https://www.ncbi.nlm.nih.gov/pubmed/29142246

Abstract

The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

PMID:

29142246

PMCID:

PMC5688067

DOI:

10.1038/s41467-017-01642-w

[Indexed for MEDLINE]

Free PMC Article

FIGURE
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688067/figure/Fig1/

NUDT22(11q13.1) UDP-glucose- and UDP-galactose hydrolase

https://www.ncbi.nlm.nih.gov/gene/84304

Expression

Ubiquitous expression in duodenum (RPKM 16.3), spleen (RPKM 14.4) and 25 other tissues See more

Orthologs

mouse all

Related articles in PubMed

1. Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold. Carter M, et al. Structure, 2018 Feb 6. PMID 29413322Abstract
   Human NUDT22 belongs to the diverse NUDIX family of proteins, but has, until now, remained uncharacterized. Here we show that human NUDT22 is a Mg²⁺-dependent UDP-glucose and UDP-galactose hydrolase, producing UMP and glucose 1-phosphate or galactose 1-phosphate. We present the structure of human NUDT22 alone and in a complex with the substrate UDP-glucose. These structures reveal a partially conserved NUDIX fold domain preceded by a unique N-terminal domain responsible for UDP moiety binding and recognition. The NUDIX domain of NUDT22 contains a modified NUDIX box identified using structural analysis and confirmed through functional analysis of mutants. Human NUDT22's distinct structure and function as a UDP-carbohydrate hydrolase establish a unique NUDIX protein subfamily.
2. Genome-wide association study of the child behavior checklist dysregulation profile. Mick E, et al. J Am Acad Child Adolesc Psychiatry, 2011 Aug. PMID 21784300, Free PMC Article
3. New genetic associations detected in a host response study to hepatitis B vaccine. Davila S, et al. Genes Immun, 2010 Apr. PMID 20237496
4. Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study. Bailey SD, et al. Diabetes Care, 2010 Oct. PMID 20628086, Free PMC Article
5. Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Talmud PJ, et al. Am J Hum Genet, 2009 Nov. PMID 19913121, Free PMC Article

See all (11) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

NUDT21 (16q13), CFIM, CPSFS , cleavage and polyadenylation specifity factor subunit 5

https://www.ncbi.nlm.nih.gov/gene/11051
 The protein encoded by this gene is one subunit of a cleavage factor required for 3' RNA cleavage and polyadenylation processing. The interaction of the protein with the RNA is one of the earliest steps in the assembly of the 3' end processing complex and facilitates the recruitment of other processing factors. This gene encodes the 25kD subunit of the protein complex, which is composed of four polypeptides. [provided by RefSeq, Jul 2008]

Preferred Names

cleavage and polyadenylation specificity factor subunit 5

Names

CPSF 25 kDa subunit

cleavage and polyadenylation specific factor 5, 25 kD subunit

cleavage and polyadenylation specific factor 5, 25 kDa

cleavage and polyadenylation specificity factor 25 kDa subunit

cleavage factor Im complex 25 kDa subunit

nucleoside diphosphate-linked moiety X motif 21

nudix (nucleoside diphosphate linked moiety X)-type motif 21

nudix motif 21

pre-mRNA cleavage factor Im (25kD)

pre-mRNA cleavage factor Im 25 kDa subunit

pre-mRNA cleavage factor Im 68 kDa subunit

pre-mRNA cleavage factor Im, 25kD subunit

Related articles in PubMed

1. NUDT21 regulates 3'-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. Sun M, et al. Cancer Lett, 2017 Dec 1. PMID 28964783
2. The crystal structure of human cleavage and polyadenylation specific factor-5 reveals a dimeric Nudix protein with a conserved catalytic site. Trésaugues L, et al. Proteins, 2008 Dec. PMID 18767156
3. Crystal structure of the 25 kDa subunit of human cleavage factor Im. Coseno M, et al. Nucleic Acids Res, 2008 Jun. PMID 18445629, Free PMC Article
4. RNAcompete methodology and application to determine sequence preferences of unconventional RNA-binding proteins. Ray D, et al. Methods, 2017 Apr 15. PMID 27956239, Free PMC Article
5. MicroRNA-181a promotes proliferation and inhibits apoptosis by suppressing CFIm25 in osteosarcoma. Zhu ZJ, et al. Mol Med Rep, 2016 Nov. PMID 27633853

See all (81) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

1. RNA sequence preferences of unconventional RNA-binding proteins, Nudt21 and CNBP, has been described.
2. Loss of NUDT21 shortened the 3'-UTR of various oncogenes in hepatocellular carcinoma cells. The shorter 3'-UTR contained less miRNA binding sites, which enabled the oncogenes to evade miRNA regulation and become overexpressed in HCC, leading to unregulated cancer cell proliferation.
3. it was demonstrated that the CFIm25 protein was also downregulated in osteosarcoma tissues, and inhibited the proliferation and promoted the apoptosis of the cells. Elucidating the roles of miR181a and CFIm25 in osteosarcoma not only assists in further understanding the pathogenesis and progression of this disease, but also offers novel targets for effective therapies.
4. The authors identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation.
5. Structure of a CFI(m)25/CFI(m)68 RRM heterotetramer and biochemical data indicated that CFIm25 specifically recognized two UGUA elements, CFIm68 facilitates looping of the intervening RNA. CFIm-mediated RNA looping may regulate alternative polyadnylation.
6. Crystal structure of CFIm25-CFIm68 RRM heterotetramer illustrated that CFIm25 homodimer is clamped by two CFIm68 monomers on each side of the dimer interface.
7. Data provide evidence that CFIm exists as a heterotetramer of 25-kD, 59-kD and 68-kD subunits of CFIm: CFIm25, CFIm59 and CFIm68.
8. crystal structures of the CFI(m)25 homodimer in complex with UGUAAA and UUGUAU RNA sequences
9. Crystallographic and biochemical experiments suggest that CF I(m)25 specifically recognizes UGUA RNA sequence and binds to two UGUA simultaneously
10. The crystal structure of human CPSF5 was solved at 1.9 A resolution.

Submit: New GeneRIF Correction See all GeneRIFs (13)

mRNA decapping , Multiplle decapping enzymes exist

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939969/

Best matches for mRNA decapping:

New insights into decapping enzymes and selective mRNA decay.  

Grudzien-Nogalska E et al. Wiley Interdiscip Rev RNA. (2017)

 Abstract

Removal of the 5' end cap is a critical determinant controlling mRNA stability and efficient gene expression. Removal of the cap is exquisitely controlled by multiple direct and indirect regulators that influence association with the cap and the catalytic step. A subset of these factors directly stimulate activity of the decapping enzyme, while others influence remodeling of factors bound to mRNA and indirectly stimulate decapping. Furthermore, the components of the general decapping machinery can also be recruited by mRNA-specific regulatory proteins to activate decapping. 

 The Nudix hydrolase, Dcp2, identified as a first decapping enzyme, cleaves capped mRNA and initiates 5'-3' degradation. Extensive studies on Dcp2 led to broad understanding of its activity and the regulation of transcript specific decapping and decay.
 Interestingly, seven additional Nudix proteins possess intrinsic decapping activity in vitro and at least two, Nudt16 and Nudt3, are decapping enzymes that regulate mRNA stability in cells.

Furthermore, a new class of decapping proteins within the DXO family preferentially function on incompletely capped mRNAs. Importantly, it is now evident that each of the characterized decapping enzymes predominantly modulates only a subset of mRNAs, suggesting the existence of multiple decapping enzymes functioning in distinct cellular pathways.
 WIREs RNA 2017, 8:e1379. doi: 10.1002/wrna.1379 For further resources related to this article, please visit the WIREs website.PMID:27425147PMCID:PMC5179306DOI:10.1002/wrna.1379

 

A human microprotein that interacts with the mRNA decapping complex.  

D'Lima NG et al. Nat Chem Biol. (2017)

 

Mille viae in eukaryotic mRNA decapping.  

Valkov E et al. Curr Opin Struct Biol. (2017)