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PAFAH1B1  -  platelet-activating factor acetylhydrolase...

Homo sapiens

Synonyms: LIS-1, LIS1, LIS2, Lissencephaly-1 protein, MDCR, ...
 
 
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Disease relevance of PAFAH1B1

 

Psychiatry related information on PAFAH1B1

 

High impact information on PAFAH1B1

  • Lis1 associates with microtubules and modulates neuronal migration [8].
  • Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans [9].
  • Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth [10].
  • The protein encoded by this gene is 2,156 amino acids and its function is currently unknown, although the amino terminus has similarity to that of the doublecortin protein, whose gene (DCX) has been implicated in lissencephaly in humans [11].
  • Heterozygous mutation or deletion of the beta subunit of platelet-activating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration [12].
 

Chemical compound and disease context of PAFAH1B1

 

Biological context of PAFAH1B1

  • About 15% of patients with isolated lissencephaly and more than 90% of patients with Miller-Dieker syndrome have microdeletions in a critical 350-kilobase region in chromosome 17p13.3 (ref. 6). These deletions are hemizygous, so haplo-insufficiency for a gene in this interval is implicated [17].
  • Here we characterize NUDEL, a novel LIS1-interacting protein with sequence homology to gene products also implicated in nuclear distribution in fungi [18].
  • We previously reported that mammalian LIS1 functions in cell division and coimmunoprecipitates with cytoplasmic dynein and dynactin [5].
  • We now find that the COOH-terminal WD repeat region of LIS1 is sufficient for kinetochore targeting [5].
  • Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS [19].
 

Anatomical context of PAFAH1B1

  • Like LIS1, NUDEL is robustly expressed in brain, enriched at centrosomes and neuronal growth cones, and interacts with cytoplasmic dynein [18].
  • Surprisingly, LIS2 detected an additional, higher molecular weight transcript in adult skeletal muscle [20].
  • Finally, pattern formation requires the integrity of the external limiting membrane, defects of which lead to overmigration of neurons in meninges and to human type 2 lissencephaly [21].
  • Lissencephaly with agenesis of the corpus callosum and rudimentary dysplastic cerebellum may represent a subset of lissencephaly with cerebellar hypoplasia (LCH) of unknown etiology, one that is distinct from other types of LCH [22].
  • Mutations of the ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype-phenotype correlation [23].
 

Associations of PAFAH1B1 with chemical compounds

  • The NH2-terminal self-association domain of LIS1 displaces endogenous LIS1 from the kinetochore, with no effect on CLIP-170, dynein, and dynactin [5].
  • We found that depletion of LIS1 pathway components resulted in defective GABA synaptic vesicle trafficking [24].
  • Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment [24].
  • Platelet-activating factor (PAF), which has been implicated in the pathophysiology of inflammation in asthma, is degraded and inactivated by PAF acetylhydrolase (PAFAH) [25].
  • All had severe type I lissencephaly with grossly normal cerebellum and a distinctive facial appearance consisting of prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw [26].
 

Physical interactions of PAFAH1B1

  • Truncated PAFAH1B3 protein lost its potential to interact with LIS1 whereas CLK2 activity was conserved within the fusion protein [27].
  • NDEL1 is a binding partner of LIS1 that participates in the regulation of cytoplasmic dynein function and microtubule organization during mitotic cell division and neuronal migration [28].
  • Furthermore, endogenous DCX could be co-immunoprecipitated with endogenous LIS1 in embryonic brain extracts, demonstrating an in vivo association [29].
  • Lissencephaly type I has been described as either the cerebral expression of a complex malformation syndrome such as Miller-Dieker syndrome (MDS), or as isolated lissencephaly sequence (ILS) [30].
 

Regulatory relationships of PAFAH1B1

  • Epitope-tagged DCX transiently expressed in COS cells can be co-immunoprecipitated with endogenous LIS1 [29].
 

Other interactions of PAFAH1B1

  • The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration [6].
  • Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized by classical lissencephaly and a characteristic facies [19].
  • Its gamma-subunit (which, formerly, we called the 29-kDa subunit) acts as a catalytic subunit, whereas the alpha-subunit (45 kDa) is the bovine homolog of the product of human LIS-1, the causative gene of Miller-Dieker lissencephaly, indicating that this intracellular PAF acetylhydrolase plays a key role in brain development [31].
  • Emerging evidence supports the idea that a signaling pathway containing orthologs of at least mammalian NudE and Nudel, Lis1, and cytoplasmic dynein is conserved for eukaryotic nuclear migration [32].
  • These results suggest that the increases in plasma type II PLA2 and PAFAH are related to vascular endothelial disorders in patients with infected burns [33].
 

Analytical, diagnostic and therapeutic context of PAFAH1B1

  • Sequence analysis revealed a striking identity (99%) of the subunit with a protein encoded by the causative gene (LIS-1) for Miller-Dieker lissencephaly, a human brain malformation manifested by a smooth cerebral surface and abnormal neuronal migration [34].
  • We find that of 12 distinct dynein and dynactin subunits, the dynein heavy and intermediate chains, as well as dynamitin, interact with the WD repeat region of LIS1 in coexpression/coimmunoprecipitation and two-hybrid assays [5].
  • Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene [19].
  • Mutations of LIS1 were found by sequencing ( n = 8) and Southern blot ( n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%) [6].
  • In type I or classical lissencephaly, two genetic causes, namely the LIS1 gene mapping at 17p13.3 and the DCX (doublecortin on X) gene mapping at Xq22.3 are involved [35].

References

  1. Genetic malformations of the cerebral cortex and epilepsy. Guerrini, R. Epilepsia (2005) [Pubmed]
  2. LIS1 association with dynactin is required for nuclear motility and genomic union in the fertilized mammalian oocyte. Payne, C., St John, J.C., Ramalho-Santos, J., Schatten, G. Cell Motil. Cytoskeleton (2003) [Pubmed]
  3. Lissencephaly 1 linking to multiple diseases: mental retardation, neurodegeneration, schizophrenia, male sterility, and more. Reiner, O., Sapoznik, S., Sapir, T. Neuromolecular Med. (2006) [Pubmed]
  4. Poliovirus protein 3A binds and inactivates LIS1, causing block of membrane protein trafficking and deregulation of cell division. Kondratova, A.A., Neznanov, N., Kondratov, R.V., Gudkov, A.V. Cell Cycle (2005) [Pubmed]
  5. Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function. Tai, C.Y., Dujardin, D.L., Faulkner, N.E., Vallee, R.B. J. Cell Biol. (2002) [Pubmed]
  6. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Pilz, D.T., Matsumoto, N., Minnerath, S., Mills, P., Gleeson, J.G., Allen, K.M., Walsh, C.A., Barkovich, A.J., Dobyns, W.B., Ledbetter, D.H., Ross, M.E. Hum. Mol. Genet. (1998) [Pubmed]
  7. Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly. Fatemi, S.H. Mol. Psychiatry (2001) [Pubmed]
  8. Interaction of reelin signaling and Lis1 in brain development. Assadi, A.H., Zhang, G., Beffert, U., McNeil, R.S., Renfro, A.L., Niu, S., Quattrocchi, C.C., Antalffy, B.A., Sheldon, M., Armstrong, D.D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G.D. Nat. Genet. (2003) [Pubmed]
  9. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Kitamura, K., Yanazawa, M., Sugiyama, N., Miura, H., Iizuka-Kogo, A., Kusaka, M., Omichi, K., Suzuki, R., Kato-Fukui, Y., Kamiirisa, K., Matsuo, M., Kamijo, S., Kasahara, M., Yoshioka, H., Ogata, T., Fukuda, T., Kondo, I., Kato, M., Dobyns, W.B., Yokoyama, M., Morohashi, K. Nat. Genet. (2002) [Pubmed]
  10. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Hong, S.E., Shugart, Y.Y., Huang, D.T., Shahwan, S.A., Grant, P.E., Hourihane, J.O., Martin, N.D., Walsh, C.A. Nat. Genet. (2000) [Pubmed]
  11. Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Sullivan, L.S., Heckenlively, J.R., Bowne, S.J., Zuo, J., Hide, W.A., Gal, A., Denton, M., Inglehearn, C.F., Blanton, S.H., Daiger, S.P. Nat. Genet. (1999) [Pubmed]
  12. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Hirotsune, S., Fleck, M.W., Gambello, M.J., Bix, G.J., Chen, A., Clark, G.D., Ledbetter, D.H., McBain, C.J., Wynshaw-Boris, A. Nat. Genet. (1998) [Pubmed]
  13. Increased plasma level of platelet-activating factor (PAF) and decreased serum PAF acetylhydrolase (PAFAH) activity in adults with bronchial asthma. Tsukioka, K., Matsuzaki, M., Nakamata, M., Kayahara, H., Nakagawa, T. Journal of investigational allergology & clinical immunology : official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología. (1996) [Pubmed]
  14. PAF acetylhydrolase and arachidonic acid metabolite levels in patients with sepsis. Takakuwa, T., Endo, S., Nakae, H., Kikichi, M., Inada, K., Yoshida, M. Res. Commun. Chem. Pathol. Pharmacol. (1994) [Pubmed]
  15. Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Takakuwa, T., Endo, S., Nakae, H., Suzuki, T., Inada, K., Yoshida, M., Ogawa, M., Uchida, K. Res. Commun. Chem. Pathol. Pharmacol. (1994) [Pubmed]
  16. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Lindhout, D., Omtzigt, J.G., Cornel, M.C. Neurology (1992) [Pubmed]
  17. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W.B., Caskey, C.T., Ledbetter, D.H. Nature (1993) [Pubmed]
  18. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Niethammer, M., Smith, D.S., Ayala, R., Peng, J., Ko, J., Lee, M.S., Morabito, M., Tsai, L.H. Neuron (2000) [Pubmed]
  19. A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Chong, S.S., Pack, S.D., Roschke, A.V., Tanigami, A., Carrozzo, R., Smith, A.C., Dobyns, W.B., Ledbetter, D.H. Hum. Mol. Genet. (1997) [Pubmed]
  20. LIS2, gene and pseudogene, homologous to LIS1 (lissencephaly 1), located on the short and long arms of chromosome 2. Reiner, O., Bar-Am, I., Sapir, T., Shmueli, O., Carrozzo, R., Lindsay, E.A., Baldini, A., Ledbetter, D.H., Cahana, A. Genomics (1995) [Pubmed]
  21. Neuronal migration. Lambert de Rouvroit, C., Goffinet, A.M. Mech. Dev. (2001) [Pubmed]
  22. Lissencephaly with agenesis of corpus callosum and rudimentary dysplastic cerebellum: a subtype of lissencephaly with cerebellar hypoplasia. Miyata, H., Chute, D.J., Fink, J., Villablanca, P., Vinters, H.V. Acta Neuropathol. (2004) [Pubmed]
  23. A new paradigm for West syndrome based on molecular and cell biology. Kato, M. Epilepsy Res. (2006) [Pubmed]
  24. Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans. Locke, C.J., Williams, S.N., Schwarz, E.M., Caldwell, G.A., Caldwell, K.A. Brain Res. (2006) [Pubmed]
  25. Evidence for an association between plasma platelet-activating factor acetylhydrolase deficiency and increased risk of childhood atopic asthma. Ito, S., Noguchi, E., Shibasaki, M., Yamakawa-Kobayashi, K., Watanabe, H., Arinami, T. J. Hum. Genet. (2002) [Pubmed]
  26. Clinical and molecular diagnosis of Miller-Dieker syndrome. Dobyns, W.B., Curry, C.J., Hoyme, H.E., Turlington, L., Ledbetter, D.H. Am. J. Hum. Genet. (1991) [Pubmed]
  27. Functional hemizygosity of PAFAH1B3 due to a PAFAH1B3-CLK2 fusion gene in a female with mental retardation, ataxia and atrophy of the brain. Nothwang, H.G., Kim, H.G., Aoki, J., Geisterfer, M., Kübart, S., Wegner, R.D., van Moers, A., Ashworth, L.K., Haaf, T., Bell, J., Arai, H., Tommerup, N., Ropers, H.H., Wirth, J. Hum. Mol. Genet. (2001) [Pubmed]
  28. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment. Mori, D., Yano, Y., Toyo-oka, K., Yoshida, N., Yamada, M., Muramatsu, M., Zhang, D., Saya, H., Toyoshima, Y.Y., Kinoshita, K., Wynshaw-Boris, A., Hirotsune, S. Mol. Cell. Biol. (2007) [Pubmed]
  29. Interaction between LIS1 and doublecortin, two lissencephaly gene products. Caspi, M., Atlas, R., Kantor, A., Sapir, T., Reiner, O. Hum. Mol. Genet. (2000) [Pubmed]
  30. Diagnostic features and clinical signs of 21 patients with lissencephaly type 1. de Rijk-van Andel, J.F., Arts, W.F., Barth, P.G., Loonen, M.C. Developmental medicine and child neurology. (1990) [Pubmed]
  31. Cloning and expression of a cDNA encoding the beta-subunit (30-kDa subunit) of bovine brain platelet-activating factor acetylhydrolase. Hattori, M., Adachi, H., Aoki, J., Tsujimoto, M., Arai, H., Inoue, K. J. Biol. Chem. (1995) [Pubmed]
  32. Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle. Yan, X., Li, F., Liang, Y., Shen, Y., Zhao, X., Huang, Q., Zhu, X. Mol. Cell. Biol. (2003) [Pubmed]
  33. Relationship between plasma levels of type II phospholipase A2, PAF acetylhydrolase, endothelin-1, and thrombomodulin in patients with infected burns. Takakuwa, T., Endo, S., Nakae, H., Yamada, Y., Inada, K., Yoshida, M., Ogawa, M., Uchida, K. Res. Commun. Mol. Pathol. Pharmacol. (1994) [Pubmed]
  34. Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase [corrected]. Hattori, M., Adachi, H., Tsujimoto, M., Arai, H., Inoue, K. Nature (1994) [Pubmed]
  35. Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. Viot, G., Sonigo, P., Simon, I., Simon-Bouy, B., Chadeyron, F., Beldjord, C., Tantau, J., Martinovic, J., Esculpavit, C., Brunelle, F., Munnich, A., Vekemans, M., Encha-Razavi, F. Am. J. Med. Genet. A (2004) [Pubmed]
 
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