5xr1

Structural highlights

Disease

FLNA_HUMAN Defects in FLNA are the cause of periventricular nodular heterotopia type 1 (PVNH1) [MIM:300049; also called nodular heterotopia, bilateral periventricular (NHBP or BPNH). PVNH is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period.^{[1] [2] [3] [4] [5]} Defects in FLNA are the cause of periventricular nodular heterotopia type 4 (PVNH4) [MIM:300537; also known as periventricular heterotopia Ehlers-Danlos variant. PVNH4 is characterized by nodular brain heterotopia, joint hypermobility and development of aortic dilation in early adulthood. Defects in FLNA are the cause of otopalatodigital syndrome type 1 (OPD1) [MIM:311300. OPD1 is an X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum.^{[6] [7]} Defects in FLNA are the cause of otopalatodigital syndrome type 2 (OPD2) [MIM:304120; also known as cranioorodigital syndrome. OPD2 is a congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects. Defects in FLNA are the cause of frontometaphyseal dysplasia (FMD) [MIM:305620. FMD is a congenital bone disease characterized by supraorbital hyperostosis, deafness and digital anomalies.^{[8] [9]} Defects in FLNA are the cause of Melnick-Needles syndrome (MNS) [MIM:309350. MNS is a severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull.^[10] Defects in FLNA are the cause of X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX) [MIM:300048. CIIPX is characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion.^[11] Defects in FLNA are the cause of FG syndrome type 2 (FGS2) [MIM:300321. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.^[12] Defects in FLNA are the cause of terminal osseous dysplasia (TOD) [MIM:300244. A rare X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females.^[13] Defects in FLNA are the cause of cardiac valvular dysplasia X-linked (CVDX) [MIM:314400. A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets.^[14] Note=Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abonormally enlarged.ITB2_HUMAN Defects in ITGB2 are the cause of leukocyte adhesion deficiency type 1 (LAD1) [MIM:116920. LAD1 patients have recurrent bacterial infections and their leukocytes are deficient in a wide range of adhesion-dependent functions.^{[15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]}

Function

FLNA_HUMAN Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis.^[26] ITB2_HUMAN Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. Integrins alpha-M/beta-2 and alpha-X/beta-2 are receptors for the iC3b fragment of the third complement component and for fibrinogen. Integrin alpha-X/beta-2 recognizes the sequence G-P-R in fibrinogen alpha-chain. Integrin alpha-M/beta-2 recognizes P1 and P2 peptides of fibrinogen gamma chain. Integrin alpha-M/beta-2 is also a receptor for factor X. Integrin alpha-D/beta-2 is a receptor for ICAM3 and VCAM1. Triggers neutrophil transmigration during lung injury through PTK2B/PYK2-mediated activation.^[27]

References

1. ↑ Hehr U, Hehr A, Uyanik G, Phelan E, Winkler J, Reardon W. A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. J Med Genet. 2006 Jun;43(6):541-4. Epub 2005 Nov 18. PMID:16299064 doi:10.1136/jmg.2005.038505
2. ↑ Sheen VL, Dixon PH, Fox JW, Hong SE, Kinton L, Sisodiya SM, Duncan JS, Dubeau F, Scheffer IE, Schachter SC, Wilner A, Henchy R, Crino P, Kamuro K, DiMario F, Berg M, Kuzniecky R, Cole AJ, Bromfield E, Biber M, Schomer D, Wheless J, Silver K, Mochida GH, Berkovic SF, Andermann F, Andermann E, Dobyns WB, Wood NW, Walsh CA. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet. 2001 Aug 15;10(17):1775-83. PMID:11532987
3. ↑ Kakita A, Hayashi S, Moro F, Guerrini R, Ozawa T, Ono K, Kameyama S, Walsh CA, Takahashi H. Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex. Acta Neuropathol. 2002 Dec;104(6):649-57. Epub 2002 Jul 23. PMID:12410386 doi:10.1007/s00401-002-0594-9
4. ↑ Moro F, Carrozzo R, Veggiotti P, Tortorella G, Toniolo D, Volzone A, Guerrini R. Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene. Neurology. 2002 Mar 26;58(6):916-21. PMID:11914408
5. ↑ Guerrini R, Mei D, Sisodiya S, Sicca F, Harding B, Takahashi Y, Dorn T, Yoshida A, Campistol J, Kramer G, Moro F, Dobyns WB, Parrini E. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology. 2004 Jul 13;63(1):51-6. PMID:15249610
6. ↑ Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. Epub 2003 Mar 3. PMID:12612583 doi:10.1038/ng1119
7. ↑ Hidalgo-Bravo A, Pompa-Mera EN, Kofman-Alfaro S, Gonzalez-Bonilla CR, Zenteno JC. A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation. Am J Med Genet A. 2005 Jul 15;136(2):190-3. PMID:15940695 doi:10.1002/ajmg.a.30792
8. ↑ Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. Epub 2003 Mar 3. PMID:12612583 doi:10.1038/ng1119
9. ↑ Zenker M, Nahrlich L, Sticht H, Reis A, Horn D. Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia. Am J Med Genet A. 2006 May 15;140(10):1069-73. PMID:16596676 doi:10.1002/ajmg.a.31213
10. ↑ Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. Epub 2003 Mar 3. PMID:12612583 doi:10.1038/ng1119
11. ↑ Gargiulo A, Auricchio R, Barone MV, Cotugno G, Reardon W, Milla PJ, Ballabio A, Ciccodicola A, Auricchio A. Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. Am J Hum Genet. 2007 Apr;80(4):751-8. Epub 2007 Feb 26. PMID:17357080 doi:S0002-9297(07)61110-0
12. ↑ Unger S, Mainberger A, Spitz C, Bahr A, Zeschnigk C, Zabel B, Superti-Furga A, Morris-Rosendahl DJ. Filamin A mutation is one cause of FG syndrome. Am J Med Genet A. 2007 Aug 15;143A(16):1876-9. PMID:17632775 doi:10.1002/ajmg.a.31751
13. ↑ Sun Y, Almomani R, Aten E, Celli J, van der Heijden J, Venselaar H, Robertson SP, Baroncini A, Franco B, Basel-Vanagaite L, Horii E, Drut R, Ariyurek Y, den Dunnen JT, Breuning MH. Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Am J Hum Genet. 2010 Jul 9;87(1):146-53. doi: 10.1016/j.ajhg.2010.06.008. PMID:20598277 doi:10.1016/j.ajhg.2010.06.008
14. ↑ Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, Toquet C, Roy E, McGregor L, Lynch SA, Newbury-Ecob R, Tran V, Young I, Trochu JN, Le Marec H, Schott JJ. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007 Jan 2;115(1):40-9. Epub 2006 Dec 26. PMID:17190868 doi:10.1161/CIRCULATIONAHA.106.622621
15. ↑ Ohashi Y, Yambe T, Tsuchiya S, Kikuchi H, Konno T. Familial genetic defect in a case of leukocyte adhesion deficiency. Hum Mutat. 1993;2(6):458-67. PMID:7509236 doi:http://dx.doi.org/10.1002/humu.1380020606
16. ↑ Nelson C, Rabb H, Arnaout MA. Genetic cause of leukocyte adhesion molecule deficiency. Abnormal splicing and a missense mutation in a conserved region of CD18 impair cell surface expression of beta 2 integrins. J Biol Chem. 1992 Feb 15;267(5):3351-7. PMID:1346613
17. ↑ Arnaout MA, Dana N, Gupta SK, Tenen DG, Fathallah DM. Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. J Clin Invest. 1990 Mar;85(3):977-81. PMID:1968911 doi:http://dx.doi.org/10.1172/JCI114529
18. ↑ Wardlaw AJ, Hibbs ML, Stacker SA, Springer TA. Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates. J Exp Med. 1990 Jul 1;172(1):335-45. PMID:1694220
19. ↑ Matsuura S, Kishi F, Tsukahara M, Nunoi H, Matsuda I, Kobayashi K, Kajii T. Leukocyte adhesion deficiency: identification of novel mutations in two Japanese patients with a severe form. Biochem Biophys Res Commun. 1992 May 15;184(3):1460-7. PMID:1590804
20. ↑ Corbi AL, Vara A, Ursa A, Garcia Rodriguez MC, Fontan G, Sanchez-Madrid F. Molecular basis for a severe case of leukocyte adhesion deficiency. Eur J Immunol. 1992 Jul;22(7):1877-81. PMID:1352501 doi:http://dx.doi.org/10.1002/eji.1830220730
21. ↑ Back AL, Kwok WW, Hickstein DD. Identification of two molecular defects in a child with leukocyte adherence deficiency. J Biol Chem. 1992 Mar 15;267(8):5482-7. PMID:1347532
22. ↑ Back AL, Kerkering M, Baker D, Bauer TR, Embree LJ, Hickstein DD. A point mutation associated with leukocyte adhesion deficiency type 1 of moderate severity. Biochem Biophys Res Commun. 1993 Jun 30;193(3):912-8. PMID:7686755 doi:http://dx.doi.org/10.1006/bbrc.1993.1712
23. ↑ Hogg N, Stewart MP, Scarth SL, Newton R, Shaw JM, Law SK, Klein N. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest. 1999 Jan;103(1):97-106. PMID:9884339 doi:10.1172/JCI3312
24. ↑ Li L, Jin YY, Cao RM, Chen TX. A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient. Chin Med J (Engl). 2010 May 20;123(10):1278-82. PMID:20529581
25. ↑ Parvaneh N, Mamishi S, Rezaei A, Rezaei N, Tamizifar B, Parvaneh L, Sherkat R, Ghalehbaghi B, Kashef S, Chavoshzadeh Z, Isaeian A, Ashrafi F, Aghamohammadi A. Characterization of 11 new cases of leukocyte adhesion deficiency type 1 with seven novel mutations in the ITGB2 gene. J Clin Immunol. 2010 Sep;30(5):756-60. doi: 10.1007/s10875-010-9433-2. Epub 2010 , Jun 12. PMID:20549317 doi:10.1007/s10875-010-9433-2
26. ↑ Adams M, Simms RJ, Abdelhamed Z, Dawe HR, Szymanska K, Logan CV, Wheway G, Pitt E, Gull K, Knowles MA, Blair E, Cross SH, Sayer JA, Johnson CA. A meckelin-filamin A interaction mediates ciliogenesis. Hum Mol Genet. 2012 Mar 15;21(6):1272-86. doi: 10.1093/hmg/ddr557. Epub 2011 Nov , 25. PMID:22121117 doi:10.1093/hmg/ddr557
27. ↑ Xu J, Gao XP, Ramchandran R, Zhao YY, Vogel SM, Malik AB. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating beta2 integrins. Nat Immunol. 2008 Aug;9(8):880-6. doi: 10.1038/ni.1628. Epub 2008 Jun 29. PMID:18587400 doi:10.1038/ni.1628