5ms9

Structural highlights

Disease

FBN1_HUMAN Defects in FBN1 are a cause of Marfan syndrome (MFS) [MIM:154700. MFS is an autosomal dominant disorder that affects the skeletal, ocular, and cardiovascular systems. A wide variety of skeletal abnormalities occurs with MFS, including scoliosis, chest wall deformity, tall stature, abnormal joint mobility. Ectopia lentis occurs in up to about 80% of MFS patients and is almost always bilateral. The leading cause of premature death in MFS patients is progressive dilation of the aortic root and ascending aorta, causing aortic incompetence and dissection. Note=The majority of the more than 600 mutations in FBN1 currently known are point mutations, the rest are frameshifts and splice site mutations. Marfan syndrome has been suggested in at least 2 historical figures, Abraham Lincoln and Paganini.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]} Defects in FBN1 are a cause of ectopia lentis, isolated, autosomal dominant (ECTOL1) [MIM:129600. An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation.^{[34] [35] [36] [37]} Defects in FBN1 are the cause of Weill-Marchesani syndrome 2 (WMS2) [MIM:608328. A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma.^[38] Defects in FBN1 are a cause of Shprintzen-Goldberg craniosynostosis syndrome (SGS) [MIM:182212. SGS is a very rare syndrome characterized by a marfanoid habitus, craniosynostosis, characteristic dysmorphic facial features, skeletal and cardiovascular abnormalities, mental retardation, developmental delay and learning disabilities.[:] Defects in FBN1 are a cause of overlap connective tissue disease (OCTD) [MIM:604308. A heritable disorder of connective tissue characterized by involvement of the mitral valve, aorta, skeleton, and skin. MASS syndrome is closely resembling both the Marfan syndrome and the Barlow syndrome. However, no dislocation of the lenses or aneurysmal changes occur in the aorta, and the mitral valve prolapse is by no means invariable.^[39] Defects in FBN1 are a cause of stiff skin syndrome (SSKS) [MIM:184900. It is a syndrome characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness.^[40] Defects in FBN1 are the cause of geleophysic dysplasia type 2 (GPHYSD2) [MIM:614185. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues.^[41] Defects in FBN1 are the cause of acromicric dysplasia (ACMICD) [MIM:102370. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal.^[42]

Function

FBN1_HUMAN Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-1-containing microfibrils provide long-term force bearing structural support. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity).^[43]

References

1. ↑ Uyeda T, Takahashi T, Eto S, Sato T, Xu G, Kanezaki R, Toki T, Yonesaka S, Ito E. Three novel mutations of the fibrillin-1 gene and ten single nucleotide polymorphisms of the fibrillin-3 gene in Marfan syndrome patients. J Hum Genet. 2004;49(8):404-7. Epub 2004 Jun 23. PMID:15221638 doi:10.1007/s10038-004-0168-x
2. ↑ Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, et al.. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991 Jul 25;352(6333):337-9. PMID:1852208 doi:http://dx.doi.org/10.1038/352337a0
3. ↑ Dietz HC, Saraiva JM, Pyeritz RE, Cutting GR, Francomano CA. Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum Mutat. 1992;1(5):366-74. PMID:1301946 doi:http://dx.doi.org/10.1002/humu.1380010504
4. ↑ Dietz HC, Pyeritz RE, Puffenberger EG, Kendzior RJ Jr, Corson GM, Maslen CL, Sakai LY, Francomano CA, Cutting GR. Marfan phenotype variability in a family segregating a missense mutation in the epidermal growth factor-like motif of the fibrillin gene. J Clin Invest. 1992 May;89(5):1674-80. PMID:1569206 doi:http://dx.doi.org/10.1172/JCI115766
5. ↑ Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, Francomano CA. Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics. 1993 Aug;17(2):468-75. PMID:8406497 doi:http://dx.doi.org/10.1006/geno.1993.1349
6. ↑ Hewett DR, Lynch JR, Smith R, Sykes BC. A novel fibrillin mutation in the Marfan syndrome which could disrupt calcium binding of the epidermal growth factor-like module. Hum Mol Genet. 1993 Apr;2(4):475-7. PMID:8504310
7. ↑ Tynan K, Comeau K, Pearson M, Wilgenbus P, Levitt D, Gasner C, Berg MA, Miller DC, Francke U. Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. Hum Mol Genet. 1993 Nov;2(11):1813-21. PMID:8281141
8. ↑ Karttunen L, Raghunath M, Lonnqvist L, Peltonen L. A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype. Am J Hum Genet. 1994 Dec;55(6):1083-91. PMID:7977366
9. ↑ Hayward C, Rae AL, Porteous ME, Logie LJ, Brock DJ. Two novel mutations and a neutral polymorphism in EGF-like domains of the fibrillin gene (FBN1): SSCP screening of exons 15-21 in Marfan syndrome patients. Hum Mol Genet. 1994 Feb;3(2):373-5. PMID:8004112
10. ↑ Stahl-Hallengren C, Ukkonen T, Kainulainen K, Kristofersson U, Saxne T, Tornqvist K, Peltonen L. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. J Clin Invest. 1994 Aug;94(2):709-13. PMID:8040326 doi:http://dx.doi.org/10.1172/JCI117389
11. ↑ Hewett DR, Lynch JR, Child A, Sykes BC. A new missense mutation of fibrillin in a patient with Marfan syndrome. J Med Genet. 1994 Apr;31(4):338-9. PMID:8071963
12. ↑ Hayward C, Porteous ME, Brock DJ. A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mol Cell Probes. 1994 Aug;8(4):325-7. PMID:7870075 doi:http://dx.doi.org/10.1006/mcpr.1994.1045
13. ↑ Kainulainen K, Karttunen L, Puhakka L, Sakai L, Peltonen L. Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome. Nat Genet. 1994 Jan;6(1):64-9. PMID:8136837 doi:http://dx.doi.org/10.1038/ng0194-64
14. ↑ Nijbroek G, Sood S, McIntosh I, Francomano CA, Bull E, Pereira L, Ramirez F, Pyeritz RE, Dietz HC. Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Am J Hum Genet. 1995 Jul;57(1):8-21. PMID:7611299
15. ↑ Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Invest. 1995 May;95(5):2373-8. PMID:7738200 doi:http://dx.doi.org/10.1172/JCI117930
16. ↑ Putnam EA, Cho M, Zinn AB, Towbin JA, Byers PH, Milewicz DM. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. Am J Med Genet. 1996 Mar 29;62(3):233-42. PMID:8882780 doi:<233::AID-AJMG7>3.0.CO;2-U 10.1002/(SICI)1096-8628(19960329)62:3<233::AID-AJMG7>3.0.CO;2-U
17. ↑ Ades LC, Haan EA, Colley AF, Richard RI. Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome. J Med Genet. 1996 Aug;33(8):665-71. PMID:8863159
18. ↑ Booms P, Withers AP, Boxer M, Kaufmann UC, Hagemeier C, Vetter U, Robinson PN. A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype. Hum Genet. 1997 Aug;100(2):195-200. PMID:9254848
19. ↑ Hayward C, Porteous ME, Brock DJ. Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: report of 12 novel mutations. Hum Mutat. 1997;10(4):280-9. PMID:9338581 doi:<280::AID-HUMU3>3.0.CO;2-L 10.1002/(SICI)1098-1004(1997)10:4<280::AID-HUMU3>3.0.CO;2-L
20. ↑ Montgomery RA, Geraghty MT, Bull E, Gelb BD, Johnson M, McIntosh I, Francomano CA, Dietz HC. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec;63(6):1703-11. PMID:9837823 doi:10.1086/302144
21. ↑ Black C, Withers AP, Gray JR, Bridges AB, Craig A, Baty DU, Boxer M. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998;Suppl 1:S198-200. PMID:9452085
22. ↑ Grau U, Klein HG, Detter C, Mair H, Welz A, Seidel D, Reichart B. A novel mutation in the neonatal region of the fibrillin (FBN)1 gene associated with a classical phenotype of Marfan syndrome (MfS). Mutations in brief no. 163. Online. Hum Mutat. 1998;12(2):137. PMID:10694921 doi:<137::AID-HUMU14>3.0.CO;2-P 10.1002/(SICI)1098-1004(1998)12:2<137::AID-HUMU14>3.0.CO;2-P
23. ↑ Collod-Beroud G, Lackmy-Port-Lys M, Jondeau G, Mathieu M, Maingourd Y, Coulon M, Guillotel M, Junien C, Boileau C. Demonstration of the recurrence of Marfan-like skeletal and cardiovascular manifestations due to germline mosaicism for an FBN1 mutation. Am J Hum Genet. 1999 Sep;65(3):917-21. PMID:10441597 doi:10.1086/302545
24. ↑ El-Aleem AA, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M. Identification of 9 novel FBN1 mutations in German patients with Marfan syndrome. Hum Mutat. 1999 Aug 19;14(2):181. PMID:10425041 doi:<181::AID-HUMU10>3.0.CO;2-6 10.1002/(SICI)1098-1004(1999)14:2<181::AID-HUMU10>3.0.CO;2-6
25. ↑ Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID:11700157
26. ↑ Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Turkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. PMID:12203992 doi:10.1002/humu.10112
27. ↑ Korkko J, Kaitila I, Lonnqvist L, Peltonen L, Ala-Kokko L. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. PMID:11826022
28. ↑ Biggin A, Holman K, Brett M, Bennetts B, Ades L. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004 Jan;23(1):99. PMID:14695540 doi:10.1002/humu.9207
29. ↑ Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, Batge B, Notbohm H, Reinhardt DP. Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1. J Biol Chem. 2004 Jul 30;279(31):32924-31. Epub 2004 May 25. PMID:15161917 doi:10.1074/jbc.M405239200
30. ↑ Arbustini E, Grasso M, Ansaldi S, Malattia C, Pilotto A, Porcu E, Disabella E, Marziliano N, Pisani A, Lanzarini L, Mannarino S, Larizza D, Mosconi M, Antoniazzi E, Zoia MC, Meloni G, Magrassi L, Brega A, Bedeschi MF, Torrente I, Mari F, Tavazzi L. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mutat. 2005 Nov;26(5):494. PMID:16222657 doi:10.1002/humu.9377
31. ↑ Rommel K, Karck M, Haverich A, von Kodolitsch Y, Rybczynski M, Muller G, Singh KK, Schmidtke J, Arslan-Kirchner M. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat. 2005 Dec;26(6):529-39. PMID:16220557 doi:10.1002/humu.20239
32. ↑ Barnett CP, Wilson GJ, Chiasson DA, Gross GJ, Hinek A, Hawkins C, Chitayat D. Central nervous system abnormalities in two cases with neonatal Marfan syndrome with novel mutations in the fibrillin-1 gene. Am J Med Genet A. 2010 Sep;152A(9):2409-12. doi: 10.1002/ajmg.a.33406. PMID:20803651 doi:10.1002/ajmg.a.33406
33. ↑ Baetens M, Van Laer L, De Leeneer K, Hellemans J, De Schrijver J, Van De Voorde H, Renard M, Dietz H, Lacro RV, Menten B, Van Criekinge W, De Backer J, De Paepe A, Loeys B, Coucke PJ. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011 May 3. doi: 10.1002/humu.21525. PMID:21542060 doi:10.1002/humu.21525
34. ↑ Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID:11700157
35. ↑ Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Turkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. PMID:12203992 doi:10.1002/humu.10112
36. ↑ Korkko J, Kaitila I, Lonnqvist L, Peltonen L, Ala-Kokko L. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. PMID:11826022
37. ↑ Lonnqvist L, Child A, Kainulainen K, Davidson R, Puhakka L, Peltonen L. A novel mutation of the fibrillin gene causing ectopia lentis. Genomics. 1994 Feb;19(3):573-6. PMID:8188302 doi:http://dx.doi.org/S0888-7543(84)71110-4
38. ↑ Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le Merrer M, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003 Jan;40(1):34-6. PMID:12525539
39. ↑ Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA. 1989 Jul 28;262(4):523-8. PMID:2739055
40. ↑ Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, Chillakuri CR, Macaya D, Coucke PJ, De Paepe A, Judge DP, Wigley F, Davis EC, Mardon HJ, Handford P, Keene DR, Sakai LY, Dietz HC. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010 Mar 17;2(23):23ra20. doi: 10.1126/scitranslmed.3000488. PMID:20375004 doi:10.1126/scitranslmed.3000488
41. ↑ Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y, Brady AF, Cordier MP, Devriendt K, Genevieve D, Kiper PO, Kitoh H, Krakow D, Lynch SA, Le Merrer M, Megarbane A, Mortier G, Odent S, Polak M, Rohrbach M, Sillence D, Stolte-Dijkstra I, Superti-Furga A, Rimoin DL, Topouchian V, Unger S, Zabel B, Bole-Feysot C, Nitschke P, Handford P, Casanova JL, Boileau C, Apte SS, Munnich A, Cormier-Daire V. Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011 Jul 15;89(1):7-14. doi: 10.1016/j.ajhg.2011.05.012. Epub, 2011 Jun 16. PMID:21683322 doi:10.1016/j.ajhg.2011.05.012
42. ↑ Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y, Brady AF, Cordier MP, Devriendt K, Genevieve D, Kiper PO, Kitoh H, Krakow D, Lynch SA, Le Merrer M, Megarbane A, Mortier G, Odent S, Polak M, Rohrbach M, Sillence D, Stolte-Dijkstra I, Superti-Furga A, Rimoin DL, Topouchian V, Unger S, Zabel B, Bole-Feysot C, Nitschke P, Handford P, Casanova JL, Boileau C, Apte SS, Munnich A, Cormier-Daire V. Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet. 2011 Jul 15;89(1):7-14. doi: 10.1016/j.ajhg.2011.05.012. Epub, 2011 Jun 16. PMID:21683322 doi:10.1016/j.ajhg.2011.05.012
43. ↑ Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure. 2004 Apr;12(4):717-29. PMID:15062093 doi:10.1016/j.str.2004.02.023
44. ↑ Robertson IB, Dias HF, Osuch IH, Lowe ED, Jensen SA, Redfield C, Handford PA. The N-Terminal Region of Fibrillin-1 Mediates a Bipartite Interaction with LTBP1. Structure. 2017 Aug 1;25(8):1208-1221.e5. doi: 10.1016/j.str.2017.06.003. Epub, 2017 Jun 29. PMID:28669633 doi:http://dx.doi.org/10.1016/j.str.2017.06.003