Wikipedia

Notch proteins

Notch proteinsare afamilyoftype 1 transmembrane proteinsthat form a core component of theNotch signaling pathway,which is highly conserved inanimals.The Notchextracellular domainmediates interactions with DSL familyligands,allowing it to participate injuxtacrine signaling.The Notch intracellular domain acts as atranscriptional activatorwhen in complex with CSL familytranscription factors.Members of this type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multipleepidermal growth factor(EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controllingcell fatedecisions. Much of what is known about Notch function comes from studies done inCaenorhabditis elegans(C.elegans) andDrosophila melanogaster.Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.

Notch (LNR) domain
Structure of a prototype LNR module from humanNotch 1[1]
Identifiers
SymbolNotch
PfamPF00066
InterProIPR000800
SMARTSM00004
PROSITEPS50258
OPM superfamily462
OPM protein5kzo
Membranome19
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

Discovery

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Notch was discovered in amutantDrosophilain March 1913 in the lab ofThomas Hunt Morgan.[2]This mutant emerged after several generations of crossing out and back-crossing beaded winged flies with wild type flies and was first characterized by John S. Dexter.[3]The most frequently observed phenotype in Notch mutant flies is the appearance of a concave serration at the most distal end of the wings, for which thegeneis named, accompanied by the absence of marginal bristles.[4][5]This mutant was found to be asex-linkeddominant on theX chromosomethat could only be observed in heterozygous females as it was lethal in males and homozygous females.[2]The first Notchallelewas established in 1917 by C.W. Metz and C.B. Bridges.[6]In the late 1930s, studies of flyembryogenesisdone by Donald F. Poulson provided the first indication of Notch's role in development.[7]Notch-8 mutant males exhibited a lack of the innergerm layers,theendodermandmesoderm,that resulted in failure to undergo latermorphogenesisembryonic lethality. Later studies in earlyDrosophilaneurogenesisprovided some of the first indications of Notch's roll in cell-cell signaling, as thenervous systemin Notch mutants was developed by sacrificing hypodermal cells.[8]

Starting in the 1980s researchers began to gain further insights into Notch function through genetic and molecular experiments. Genetic screens conducted inDrosophilaled to the identification of several proteins that play a central role in Notch signaling, including Enhancer of split,[8]Master mind, Delta,[9]Suppressor of Hairless (CSL),[10]and Serrate.[11]At the same time, the Notch gene was successfully sequenced[12][13]and cloned,[14][15]providing insights into the molecular architecture of Notch proteins and led to identification of NotchhomologsinCaenorhabditis elegans(C. elegans)[16][17][18]and eventually inmammals.

In the early 1990s Notch was increasingly implicated as the receptor of a previously unknown intercellular signal pathway[19][20]in which the Notch intercellular domain (NICD) is transported to thenucleuswhere it acts as atranscription factorto directly regulate target genes.[21][22][23]The release of the NICD was found to be as a result of proteolytic cleavage of the transmembrane protein through the actions of theγ-secretasecomplex catalytic subunitPresenilin.This was a significant interaction as Presenilin is implicated in the development of Alzheimer's disease.[24]This and further research into the mechanism of Notch signaling led to research that would further connect Notch to a wide range of human diseases.

Structure

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Drosophilacontain a single Notch protein,C.eleganscontain two redundant notch paralogs, Lin-12[25]and GLP-1,[18][26]and humans have four Notch variants, Notch 1-4. Although variations exist between homologs, there are a set of highly conserved structures found in all Notch family proteins. The protein can broadly be split into the Notch extracellular domain (NECD) and Notch intracellular domain (NICD) joined together by a single-pass transmembrane domain (TM).

The NECD contains 36 EGF repeats inDrosophila,[13]28-36 in humans, and 13 and 10 inC. elegansLin-12 and GLP-1 respectively.[27]These repeats are heavily modified throughO-glycoslyation[28]and the addition of specific O-linked glycans has been shown to be necessary for proper function. The EGF repeats are followed by threecysteine-rich Lin-12/Notch Repeats (LNR) and a heterodimerization (HD) domain. Together the LNR and HD compose the negative regulatory region adjacent to thecell membraneand help prevent signaling in the absence of ligand binding.

NICD acts as a transcription factor that is released after ligand binding triggers its cleavage. It contains a nuclear localization sequence (NLS) that mediates its translocation to thenucleus,where it forms a transcriptional complex along with several other transcription factors. Once in the nucleus, severalankyrin repeatsand the RAM domain interactions between the NICD and CSL proteins to form a transcriptional activation complex.[29]In humans, an additional PEST domain plays a role in NICD degradation.[30]

Function

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The Notch signaling pathway. Notch interacts with its ligands Delta or Serrate, leading to cleavage of the NICD which can then interact with Su(H) to form a transcriptional complex.

Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is anevolutionarily conservedintercellularsignaling pathwaythat regulates interactions between physically adjacent cells. InDrosophila,notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. This protein functions as a receptor for membrane bound ligands, and may play multiple roles during development.[31] A deficiency can be associated withbicuspid aortic valve.[32]

There is evidence that activated Notch 1 andNotch 3promote differentiation of progenitor cells intoastroglia.[33]Notch 1, then activated before birth, inducesradial gliadifferentiation,[34]but postnatally induces the differentiation intoastrocytes.[35]One study shows that Notch-1 cascade is activated byReelinin an unidentified way.[36]Reelin and Notch1 cooperate in the development of thedentate gyrus,according to another.[37]

Ligand interactions

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Jagged/Serrate protein
Identifiers
SymbolDSL
PfamPF01414
InterProIPR026219
Membranome76
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

Notch signaling is triggered via direct cell-to-cell contact, mediated by interactions between the Notch receptor protein in the signal receiving cell and a ligand in an adjacent signal transmitting cell. These type 1single-pass transmembrane proteinsfall into the Delta/Serrate/Lag-2 (DSL) family of proteins which is named after the three canonical Notch ligands.[19]Delta and Serrate are found inDrosophilawhile Lag-2 is found inC. elegans.Humans contain 3 Delta homologs,Delta-like 1,3,and4,as well as two Serrate homologs,Jagged 1and2.Notch proteins consist of a relatively short intracellular domain and a large extracellular domain with one or moreEGF motifsand a N-terminal DSL-binding motif. EGF repeats 11-12 on the Notch extracellular domain have been shown to be necessary and sufficient fortranssignaling interactions between Notch and its ligands.[38]Additionally, EGF repeats 24-29 have been implicated in inhibition ofcisinteractions between Notch and ligands co-expressed in the same cell.[39]

Proteolysis

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In order for a signaling event to occur, the Notch protein must be cleaved at several sites. In humans, Notch is first cleaved in the NRR domain byfurinwhile being processed in thetrans-Golgi networkbefore being presented on the cell surface as a heterodimer.[40][41]DrosophilaNotch does not require this cleavage for signaling to occur,[42]and there is some evidence that suggests that LIN-12 and GLP-1 are cleaved at this site inC. elegans.

Release of the NICD is achieved after an additional two cleavage events to Notch. Binding of Notch to a DSL ligand results in a conformational change that exposes a cleavage site in the NECD. Enzymatic proteolysis at this site is carried out by a A Disintegrin and Metalloprotease domain (ADAM) family protease. This protein is called Kuzbanian inDrosophila,[43][44]sup-17 inC. elegans,[45]and ADAM10 in humans.[46][47]After proteolytic cleavage, the released NECD is endocytosed into the signal transmitting cell, leaving behind only a small extracellular portion of Notch. This truncated Notch protein can then be recognized by a γ-secretase that cleaves the third site found in the TM domain.[48]

Human homologs

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Notch-1

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Main article:Notch 1

Notch-2

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Main article:Notch 2

Notch-2(Neurogenic locus notch homolog protein 2) is aproteinthat in humans is encoded by theNOTCH2gene.[49]

NOTCH2 is associated withAlagille syndrome[50]andHajdu–Cheney syndrome.[51]

Notch-3

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Main article:Notch 3

Notch-4

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Main article:Notch 4

See also

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Notes

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  1. ^Vardar D, North CL, Sanchez-Irizarry C, Aster JC, Blacklow SC (June 2003). "Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1".Biochemistry.42(23): 7061–7.doi:10.1021/bi034156y.PMID12795601.
  2. ^abMorgan TH, Bridges CB (1916).Sex-linked inheritance in Drosophila.NCSU Libraries. Washington, Carnegie Institution of Washington.
  3. ^Dexter JS (December 1914)."The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations".The American Naturalist.48(576): 712–758.doi:10.1086/279446.hdl:2027/nnc1.cu56096100.
  4. ^Mohr OL (May 1919)."Character Changes Caused by Mutation of an Entire Region of a Chromosome in Drosophila".Genetics.4(3): 275–82.doi:10.1093/genetics/4.3.275.PMC1200460.PMID17245926.
  5. ^Lindsley DL, Zimm GG (2012-12-02).The Genome of Drosophila Melanogaster.Academic Press.ISBN9780323139847.
  6. ^Metz CW, Bridges CB (December 1917)."Incompatibility of Mutant Races in Drosophila".Proceedings of the National Academy of Sciences of the United States of America.3(12): 673–8.Bibcode:1917PNAS....3..673M.doi:10.1073/pnas.3.12.673.PMC1091355.PMID16586764.
  7. ^Poulson DF (March 1937)."Chromosomal Deficiencies and the Embryonic Development of Drosophila Melanogaster".Proceedings of the National Academy of Sciences of the United States of America.23(3): 133–7.Bibcode:1937PNAS...23..133P.doi:10.1073/pnas.23.3.133.PMC1076884.PMID16588136.
  8. ^abLehmann R, Jiménez F, Dietrich U, Campos-Ortega JA (March 1983). "On the phenotype and development of mutants of early neurogenesis inDrosophila melanogaster".Wilhelm Roux's Archives of Developmental Biology.192(2): 62–74.doi:10.1007/BF00848482.PMID28305500.S2CID25602190.
  9. ^Lehmann R, Dietrich U, Jiménez F, Campos-Ortega JA (July 1981). "Mutations of early neurogenesis inDrosophila".Wilhelm Roux's Archives of Developmental Biology.190(4): 226–229.doi:10.1007/BF00848307.PMID28305572.S2CID21814447.
  10. ^Fortini ME, Artavanis-Tsakonas S (October 1994). "The suppressor of hairless protein participates in notch receptor signaling".Cell.79(2): 273–82.doi:10.1016/0092-8674(94)90196-1.PMID7954795.S2CID40771329.
  11. ^Fleming RJ, Scottgale TN, Diederich RJ, Artavanis-Tsakonas S (December 1990)."The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster".Genes & Development.4(12A): 2188–201.doi:10.1101/gad.4.12a.2188.PMID2125287.
  12. ^Kidd S, Kelley MR, Young MW (September 1986)."Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors".Molecular and Cellular Biology.6(9): 3094–108.doi:10.1128/mcb.6.9.3094.PMC367044.PMID3097517.
  13. ^abWharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (December 1985)."Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats".Cell.43(3 Pt 2): 567–81.doi:10.1016/0092-8674(85)90229-6.PMID3935325.
  14. ^Kidd S, Lockett TJ, Young MW (September 1983). "The Notch locus of Drosophila melanogaster".Cell.34(2): 421–33.doi:10.1016/0092-8674(83)90376-8.PMID6193889.S2CID36425372.
  15. ^Artavanis-Tsakonas S, Muskavitch MA, Yedvobnick B (April 1983)."Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster".Proceedings of the National Academy of Sciences of the United States of America.80(7): 1977–81.Bibcode:1983PNAS...80.1977A.doi:10.1073/pnas.80.7.1977.PMC393735.PMID6403942.
  16. ^Greenwald I (February 1987). "The lin-12 locus of Caenorhabditis elegans".BioEssays.6(2): 70–3.doi:10.1002/bies.950060207.PMID3551950.S2CID19253030.
  17. ^Priess JR, Schnabel H, Schnabel R (November 1987). "The glp-1 locus and cellular interactions in early C. elegans embryos".Cell.51(4): 601–11.doi:10.1016/0092-8674(87)90129-2.PMID3677169.S2CID6282210.
  18. ^abAustin J, Kimble J (November 1987). "glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans".Cell.51(4): 589–99.doi:10.1016/0092-8674(87)90128-0.PMID3677168.S2CID31484517.
  19. ^abArtavanis-Tsakonas S, Matsuno K, Fortini ME (April 1995). "Notch signaling".Science.268(5208): 225–32.Bibcode:1995Sci...268..225A.doi:10.1126/science.7716513.PMID7716513.
  20. ^Greenwald I, Rubin GM (January 1992). "Making a difference: the role of cell-cell interactions in establishing separate identities for equivalent cells".Cell.68(2): 271–81.doi:10.1016/0092-8674(92)90470-w.PMID1365402.S2CID11901508.
  21. ^Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain".Nature.393(6683): 382–6.Bibcode:1998Natur.393..382S.doi:10.1038/30756.PMID9620803.S2CID4431882.
  22. ^Kopan R, Nye JS, Weintraub H (September 1994). "The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD".Development.120(9): 2385–96.doi:10.1242/dev.120.9.2385.PMID7956819.
  23. ^Struhl G, Fitzgerald K, Greenwald I (July 1993). "Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo".Cell.74(2): 331–45.doi:10.1016/0092-8674(93)90424-o.PMID8343960.S2CID27966283.
  24. ^Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease".Nature.375(6534): 754–60.Bibcode:1995Natur.375..754S.doi:10.1038/375754a0.PMID7596406.S2CID4308372.
  25. ^Greenwald IS, Sternberg PW, Horvitz HR (September 1983). "The lin-12 locus specifies cell fates in Caenorhabditis elegans".Cell.34(2): 435–44.doi:10.1016/0092-8674(83)90377-x.PMID6616618.S2CID40668388.
  26. ^Austin J, Kimble J (August 1989). "Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans".Cell.58(3): 565–71.doi:10.1016/0092-8674(89)90437-6.PMID2758467.S2CID8514017.
  27. ^Greenwald I (December 1985)."lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor".Cell.43(3 Pt 2): 583–90.doi:10.1016/0092-8674(85)90230-2.PMID3000611.
  28. ^Shao L, Luo Y, Moloney DJ, Haltiwanger R (November 2002)."O-glycosylation of EGF repeats: identification and initial characterization of a UDP-glucose: protein O-glucosyltransferase".Glycobiology.12(11): 763–70.doi:10.1093/glycob/cwf085.PMID12460944.
  29. ^Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T (December 1995). "Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H)".Current Biology.5(12): 1416–23.doi:10.1016/S0960-9822(95)00279-X.hdl:2433/202204.PMID8749394.S2CID18442572.
  30. ^Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, et al. (October 2004). "Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia".Science.306(5694): 269–71.Bibcode:2004Sci...306..269W.doi:10.1126/science.1102160.PMID15472075.S2CID24049536.
  31. ^"Entrez Gene: NOTCH1 Notch homolog 1, translocation-associated (Drosophila)".
  32. ^McKellar SH, Tester DJ, Yagubyan M, Majumdar R, Ackerman MJ, Sundt TM (August 2007)."Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms".The Journal of Thoracic and Cardiovascular Surgery.134(2): 290–6.doi:10.1016/j.jtcvs.2007.02.041.PMID17662764.
  33. ^Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T (January 2001). "Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate".Neuron.29(1): 45–55.doi:10.1016/S0896-6273(01)00179-9.hdl:2433/150564.PMID11182080.S2CID17047028.
  34. ^Gaiano N, Nye JS, Fishell G (May 2000)."Radial glial identity is promoted by Notch1 signaling in the murine forebrain".Neuron.26(2): 395–404.doi:10.1016/S0896-6273(00)81172-1.PMID10839358.S2CID15861936.
  35. ^Chambers CB, Peng Y, Nguyen H, Gaiano N, Fishell G, Nye JS (March 2001)."Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors".Development.128(5): 689–702.doi:10.1242/dev.128.5.689.PMID11171394.
  36. ^Keilani S, Sugaya K (July 2008)."Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1".BMC Developmental Biology.8(1): 69.doi:10.1186/1471-213X-8-69.PMC2447831.PMID18593473.
  37. ^Sibbe M, Förster E, Basak O, Taylor V, Frotscher M (July 2009)."Reelin and Notch1 cooperate in the development of the dentate gyrus".The Journal of Neuroscience.29(26): 8578–85.doi:10.1523/JNEUROSCI.0958-09.2009.PMC6665659.PMID19571148.
  38. ^Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (November 1991). "Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor".Cell.67(4): 687–99.doi:10.1016/0092-8674(91)90064-6.PMID1657403.S2CID12643727.
  39. ^de Celis JF, Bray SJ (March 2000)."The Abruptex domain of Notch regulates negative interactions between Notch, its ligands and Fringe".Development.127(6): 1291–302.doi:10.1242/dev.127.6.1291.PMID10683181.
  40. ^Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S (July 1997)."Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane".Cell.90(2): 281–91.doi:10.1016/s0092-8674(00)80336-0.PMID9244302.S2CID16544864.
  41. ^Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A (July 1998)."The Notch1 receptor is cleaved constitutively by a furin-like convertase".Proceedings of the National Academy of Sciences of the United States of America.95(14): 8108–12.Bibcode:1998PNAS...95.8108L.doi:10.1073/pnas.95.14.8108.PMC20937.PMID9653148.
  42. ^Kidd S, Lieber T (July 2002)."Furin cleavage is not a requirement for Drosophila Notch function".Mechanisms of Development.115(1–2): 41–51.doi:10.1016/s0925-4773(02)00120-x.PMID12049766.S2CID10249987.
  43. ^Rooke J, Pan D, Xu T, Rubin GM (August 1996). "KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis".Science.273(5279): 1227–31.Bibcode:1996Sci...273.1227R.doi:10.1126/science.273.5279.1227.PMID8703057.S2CID10984937.
  44. ^Pan D, Rubin GM (July 1997)."Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis".Cell.90(2): 271–80.doi:10.1016/s0092-8674(00)80335-9.PMID9244301.S2CID18819481.
  45. ^Wen C, Metzstein MM, Greenwald I (December 1997). "SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling".Development.124(23): 4759–67.doi:10.1242/dev.124.23.4759.PMID9428412.
  46. ^Howard L, Glynn P (1995). "Membrane-associated metalloproteinase recognized by characteristic cleavage of myelin basic protein: Assay and isolation".Proteolytic Enzymes: Aspartic and Metallo Peptidases.Methods in Enzymology. Vol. 248. pp. 388–95.doi:10.1016/0076-6879(95)48025-0.ISBN9780121821494.PMID7545777.
  47. ^Lunn CA, Fan X, Dalie B, Miller K, Zavodny PJ, Narula SK, Lundell D (January 1997)."Purification of ADAM 10 from bovine spleen as a TNF Alpha convertase".FEBS Letters.400(3): 333–5.doi:10.1016/s0014-5793(96)01410-x.PMID9009225.S2CID83810622.
  48. ^Struhl G, Adachi A (September 2000)."Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins".Molecular Cell.6(3): 625–36.doi:10.1016/s1097-2765(00)00061-7.PMID11030342.
  49. ^Larsson C, Lardelli M, White I, Lendahl U (November 1994). "The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation".Genomics.24(2): 253–8.doi:10.1006/geno.1994.1613.PMID7698746.
  50. ^Samejima H, Torii C, Kosaki R, Kurosawa K, Yoshihashi H, Muroya K, Okamoto N, Watanabe Y, Kosho T, Kubota M, Matsuda O, Goto M, Izumi K, Takahashi T, Kosaki K (2007). "Screening for Alagille syndrome mutations in the JAG1 and NOTCH2 genes using denaturing high-performance liquid chromatography".Genetic Testing.11(3): 216–27.doi:10.1089/gte.2006.0519.PMID17949281.
  51. ^Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC (March 2011). "Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss".Nature Genetics.43(4): 303–5.doi:10.1038/ng.779.PMID21378985.S2CID205357391.

References

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This article incorporates text from the public domainPfamandInterPro:IPR000800
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