| 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.
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.[15] [ITB7_HUMAN] Integrin alpha-4/beta-7 (Peyer patches-specific homing receptor LPAM-1) is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT). Integrin alpha-4/beta-7 interacts with the cell surface adhesion molecules MADCAM1 which is normally expressed by the vascular endothelium of the gastrointestinal tract. Interacts also with VCAM1 and fibronectin, an extracellular matrix component. It recognizes one or more domains within the alternatively spliced CS-1 region of fibronectin. Interactions involves the tripeptide L-D-T in MADCAM1, and L-D-V in fibronectin. Binds to HIV-1 gp120, thereby allowing the virus to enter GALT, which is thought to be the major trigger of AIDS disease. Interaction would involve a tripeptide L-D-I in HIV-1 gp120. Integrin alpha-E/beta-7 (HML-1) is a receptor for E-cadherin.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.
The molecular basis of filamin binding to integrins and competition with talin.,Kiema T, Lad Y, Jiang P, Oxley CL, Baldassarre M, Wegener KL, Campbell ID, Ylanne J, Calderwood DA Mol Cell. 2006 Feb 3;21(3):337-47. PMID:16455489[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Kiema T, Lad Y, Jiang P, Oxley CL, Baldassarre M, Wegener KL, Campbell ID, Ylanne J, Calderwood DA. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell. 2006 Feb 3;21(3):337-47. PMID:16455489 doi:10.1016/j.molcel.2006.01.011
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