Incidental Mutation 'P0012:Fbn1'

• ID: 7566
• Institutional Source: Beutler Lab
• Gene Symbol: Fbn1
• Ensembl Gene: ENSMUSG00000027204
• Gene Name: fibrillin 1
• Synonyms: Fib-1
• MMRRC Submission: 038266-MU
• Essential gene?: Probably essential (E-score: 0.916)
• Stock #: P0012 (G1)
• Status: Validated
• Chromosome: 2
• Chromosomal Location: 125142514-125348417 bp(-) (GRCm39)
• Type of Mutation: splice site
• DNA Base Change (assembly): T to C at 125211241 bp (GRCm39)
• Zygosity: Heterozygous
• Ref Sequence: ENSEMBL: ENSMUSP00000099524
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000028633] [ENSMUST00000103234]
• AlphaFold: no structure available at present
• Predicted Effect: probably benign; Transcript: ENSMUST00000028633
• SMART Domains: Protein: ENSMUSP00000028633; Gene: ENSMUSG00000027204

Domain	Start	End	E-Value	Type
signal peptide	1	27	N/A	INTRINSIC
low complexity region	38	49	N/A	INTRINSIC
EGF	118	146	8.52e0	SMART
EGF	149	178	5.4e-2	SMART
Pfam:TB	193	235	6.9e-17	PFAM
EGF_CA	246	287	3.56e-11	SMART
EGF_CA	288	329	9.39e-11	SMART
Pfam:TB	343	388	2.3e-17	PFAM
low complexity region	394	445	N/A	INTRINSIC
EGF	454	491	8.57e-5	SMART
EGF_CA	492	531	9.39e-11	SMART
EGF_CA	532	573	2.38e-12	SMART
EGF_CA	574	614	5.48e-12	SMART
EGF_CA	615	655	5.39e-11	SMART
Pfam:TB	670	712	1.4e-17	PFAM
EGF_CA	725	766	1.53e-10	SMART
EGF_CA	767	808	2.42e-13	SMART
EGF_CA	809	848	2.44e-9	SMART
Pfam:TB	862	902	2.1e-14	PFAM
EGF_CA	912	953	3.32e-11	SMART
Pfam:TB	967	1009	3.9e-17	PFAM
EGF_CA	1030	1071	5.11e-12	SMART
EGF_CA	1072	1114	5.39e-11	SMART
EGF_CA	1115	1156	1.55e-11	SMART
EGF_CA	1157	1198	5.48e-12	SMART
EGF_CA	1199	1239	5.61e-9	SMART
EGF_CA	1240	1281	1.22e-9	SMART
EGF_CA	1282	1323	2.62e-9	SMART
EGF_CA	1324	1364	3.27e-10	SMART
EGF_CA	1365	1405	4.7e-11	SMART
EGF_CA	1406	1447	1.91e-11	SMART
EGF_CA	1448	1488	1.98e-9	SMART
EGF_CA	1489	1529	2.13e-9	SMART
Pfam:TB	1549	1590	3.5e-18	PFAM
EGF_CA	1608	1649	2.19e-11	SMART
EGF_CA	1650	1690	3.97e-9	SMART
Pfam:TB	1706	1749	9.7e-18	PFAM
EGF_CA	1768	1809	5.11e-12	SMART
EGF_CA	1810	1850	1.1e-11	SMART
EGF_CA	1851	1892	5.69e-10	SMART
EGF_CA	1893	1931	6.1e-10	SMART
EGF_CA	1932	1974	2.11e-13	SMART
EGF_CA	1975	2014	7.23e-12	SMART
EGF_CA	2015	2056	3.15e-12	SMART
Pfam:TB	2070	2112	3.7e-17	PFAM
EGF_CA	2129	2167	1.24e-10	SMART
EGF_CA	2168	2207	3.81e-11	SMART
EGF_CA	2208	2248	3.81e-11	SMART
EGF	2252	2292	5.24e0	SMART
EGF_CA	2293	2334	9.91e-10	SMART
Pfam:TB	2348	2391	8.5e-18	PFAM
EGF_CA	2404	2445	1.26e-11	SMART
EGF_CA	2446	2486	1.06e-9	SMART
EGF_CA	2487	2525	3.1e-11	SMART
EGF_CA	2526	2568	1.48e-8	SMART
EGF_CA	2569	2608	1.14e-9	SMART
EGF_CA	2609	2649	3.97e-9	SMART
EGF_CA	2650	2689	1.98e-9	SMART
low complexity region	2691	2698	N/A	INTRINSIC

• Predicted Effect: probably benign; Transcript: ENSMUST00000103234
• SMART Domains: Protein: ENSMUSP00000099524; Gene: ENSMUSG00000027204

Domain	Start	End	E-Value	Type
signal peptide	1	27	N/A	INTRINSIC
low complexity region	38	49	N/A	INTRINSIC
EGF	118	146	8.52e0	SMART
EGF	149	178	5.4e-2	SMART
Pfam:TB	194	232	3.5e-10	PFAM
EGF_CA	246	287	3.56e-11	SMART
EGF_CA	288	329	9.39e-11	SMART
Pfam:TB	344	388	6.8e-15	PFAM
low complexity region	394	445	N/A	INTRINSIC
EGF	454	491	8.57e-5	SMART
EGF_CA	492	531	9.39e-11	SMART
EGF_CA	532	573	2.38e-12	SMART
EGF_CA	574	614	5.48e-12	SMART
EGF_CA	615	655	5.39e-11	SMART
Pfam:TB	671	712	8.3e-16	PFAM
EGF_CA	725	766	1.53e-10	SMART
EGF_CA	767	808	2.42e-13	SMART
EGF_CA	809	848	2.44e-9	SMART
Pfam:TB	863	898	3.1e-8	PFAM
EGF_CA	912	953	3.32e-11	SMART
Pfam:TB	968	1009	1.5e-15	PFAM
EGF_CA	1030	1071	5.11e-12	SMART
EGF_CA	1072	1114	5.39e-11	SMART
EGF_CA	1115	1156	1.55e-11	SMART
EGF_CA	1157	1198	5.48e-12	SMART
EGF_CA	1199	1239	5.61e-9	SMART
EGF_CA	1240	1281	1.22e-9	SMART
EGF_CA	1282	1323	2.62e-9	SMART
EGF_CA	1324	1364	3.27e-10	SMART
EGF_CA	1365	1405	4.7e-11	SMART
EGF_CA	1406	1447	1.91e-11	SMART
EGF_CA	1448	1488	1.98e-9	SMART
EGF_CA	1489	1529	2.13e-9	SMART
Pfam:TB	1550	1590	5.3e-17	PFAM
EGF_CA	1608	1649	2.19e-11	SMART
EGF_CA	1650	1690	3.97e-9	SMART
Pfam:TB	1707	1749	1.6e-16	PFAM
EGF_CA	1768	1809	5.11e-12	SMART
EGF_CA	1810	1850	1.1e-11	SMART
EGF_CA	1851	1892	5.69e-10	SMART
EGF_CA	1893	1931	6.1e-10	SMART
EGF_CA	1932	1974	2.11e-13	SMART
EGF_CA	1975	2014	7.23e-12	SMART
EGF_CA	2015	2056	3.15e-12	SMART
Pfam:TB	2071	2112	1.9e-15	PFAM
EGF_CA	2129	2167	1.24e-10	SMART
EGF_CA	2168	2207	3.81e-11	SMART
EGF_CA	2208	2248	3.81e-11	SMART
EGF	2252	2292	5.24e0	SMART
EGF_CA	2293	2334	9.91e-10	SMART
Pfam:TB	2349	2391	5.8e-15	PFAM
EGF_CA	2404	2445	1.26e-11	SMART
EGF_CA	2446	2486	1.06e-9	SMART
EGF_CA	2487	2525	3.1e-11	SMART
EGF_CA	2526	2568	1.48e-8	SMART
EGF_CA	2569	2608	1.14e-9	SMART
EGF_CA	2609	2649	3.97e-9	SMART
EGF_CA	2650	2689	1.98e-9	SMART
low complexity region	2691	2698	N/A	INTRINSIC

• Coding Region Coverage:
  • 1x: 85.5%
  • 3x: 81.0%
  • 10x: 67.7%
  • 20x: 52.2%
• Validation Efficiency: 85% (579/685)
• MGI Phenotype: FUNCTION: This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Homozygous knockout mice for this gene exhibit impaired aortic development and early postnatal death, which was attributed to a deficiency in the fibrillin-1 protein. Mice with a hypomorphic allele of this gene exhibit impaired glucose homeostasis, likely due to a reduction in serum asprosin levels. [provided by RefSeq, Apr 2016] ; PHENOTYPE: Lethality among homozygotes for spontaneous and targeted mutations ranges from embryonic death to death around 4 months. Abnormalities include vascular defects, excess bone growth, connective tissue hyperplasia, and lung emphysema. Mice heterozygous for a knock-in allele exhibit scleroderma. [provided by MGI curators]
• Allele List at MGI:

  All alleles(10) : Targeted(9) Spontaneous(1)

• Posted On: 2012-10-04
• Science Writer: Anne Murray

Nature of Mutation

Three transcripts of the Fbn1 gene are displayed on Ensembl and Vega.

Protein Function and Prediction

Fibrillin (Fbn1) is a protein component of extracellular microfibrils (OMIM: *134797) and provides force-bearing structural support during late morphogenesis and the appearance of organ structures during mouse and rat development (1). The Fbn1 gene encodes 2871 amino acid structural component 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. Fibrillin 1 interacts with collagen 16A1, and forms intermolecular disulfide bonds with other fibrillin molecules. The protein contains 47 EGF-like repeats and nine TGF-beta binding (TB) domains (Uniprot Q61554).

Expression/Localization

Fbn1 is localized in both elastic and nonelastic connective tissue throughout the body (OMIM: *134797) including skin, lung, kidney, vasculature, cartilage, tendon, muscle, cornea, and ciliary zonule (2).

Background

Mutations in Fbn1 are known to cause Marfan Syndrome [MFS; OMIM: #154700; (3-5)].  Characteristics of patients with MFS have increased height, disproportionately long limbs and digits, anterior chest deformity, mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a narrow, highly arched palate with crowding of the teeth are frequent skeletal features. Some patients with FBN1 mutations and MFS also have features of Shprintzen-Goldberg syndrome [SGS; OMIM: #182212; (6)].  SGS is characterized by craniosynostosis and mental retardation. Mutations in Fbn1 have also been linked to the conditions shown in Table 1.

Table 1.  Conditions associated with mutations in FBN1.

Condition	OMIM #	Clinical Features	Refs
Acromicric dysplasia	102370	Short stature, short hands and feet, joint limitations, and thickened skin	(7)
Aortic aneurysm, ascending, and dissection			(8-10)
Ectopia lentis, familial	129600	Dislocation/displacement of the lens of the eye	(8;11-17)
Geleophysic dysplasia 2	614185	Short stature, short hands and feet, joint limitations, thickened skin,  and cardiorespiratory involvement that often leads to early death	(7)
Marfan syndrome	154700	Increased height, disproportionately long limbs and digits, anterior chest deformity, mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a narrow, highly arched palate with crowding of the teeth are frequent skeletal features	(3-5)
MASS syndrome	604308	Mitral valve prolapse, extreme dolichostenomelia, early myopia, and striae distensae but no specific features of Marfan syndrome	(18)
Stiff skin syndrome	184900	Hard, thick skin, usually over the entire body and limited joint mobility. Other occasional findings include lipodystrophy and muscle weakness	(13)
Weill-Marchesani syndrome 2, dominant	608328	A connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities	(19)

Fbn1^{tm1Rmz/tm1Rmz}; MGI:1934905

involves: 129S4/SvJae * C57BL/6J

These animals die with cardiovascular complications (i.e., aortic dissection and rupture) before weaning (~P7-P10) (20;21). These mice also have hemopericardium, heothorax, and pulmonary hemorrhage (20). At P7, dysregulation of TGF-beta activation and signaling results in increased apoptosis, but normal cell proliferation, in the developing lung (21).  Also, at P5, the average size of mutant pulmonary NEBs is ~30% smaller than that in wild-type mice, suggesting impaired neuroendocrine maturation (22).

Fbn1^{tm1Lper/tm1Lper}; MGI:4880665

involves: 129/Sv * C57BL/6 * CD-1

Similar to the model above, homozygous animals die before weaning (usually after P13) (23).

Fbn1^{tm1Lper/tm1Lper}; MGI:4880665

involves: 129/Sv * CD-1

In this genetic background, it was determined that mice die earlier and that there is partial embryonic lethality during organogenesis (i.e., after E13) (23).

References

  1. Zhang, H., Hu, W., and Ramirez, F. (1995) Developmental Expression of Fibrillin Genes Suggests Heterogeneity of Extracellular Microfibrils. J Cell Biol. 129, 1165-1176.

  2. Sakai, L. Y., Keene, D. R., and Engvall, E. (1986) Fibrillin, a New 350-kD Glycoprotein, is a Component of Extracellular Microfibrils. J Cell Biol. 103, 2499-2509.

  3. Chikumi, H., Yamamoto, T., Ohta, Y., Nanba, E., Nagata, K., Ninomiya, H., Narasaki, K., Katoh, T., Hisatome, I., Ono, K., Tanaka, Y., Kuroda, H., and Ohgi, S. (2000) Fibrillin Gene (FBN1) Mutations in Japanese Patients with Marfan Syndrome. J Hum Genet. 45, 115-118.

  4. Collod-Beroud, G., Beroud, C., Ades, L., Black, C., Boxer, M., Brock, D. J., Holman, K. J., de Paepe, A., Francke, U., Grau, U., Hayward, C., Klein, H. G., Liu, W., Nuytinck, L., Peltonen, L., Alvarez Perez, A. B., Rantamaki, T., Junien, C., and Boileau, C. (1998) Marfan Database (Third Edition): New Mutations and New Routines for the Software. Nucleic Acids Res. 26, 229-223.

  5. Collod-Beroud, G., Le Bourdelles, S., Ades, L., Ala-Kokko, L., Booms, P., Boxer, M., Child, A., Comeglio, P., De Paepe, A., Hyland, J. C., Holman, K., Kaitila, I., Loeys, B., Matyas, G., Nuytinck, L., Peltonen, L., Rantamaki, T., Robinson, P., Steinmann, B., Junien, C., Beroud, C., and Boileau, C. (2003) Update of the UMD-FBN1 Mutation Database and Creation of an FBN1 Polymorphism Database. Hum Mutat. 22, 199-208.

  6. Kosaki, K., Takahashi, D., Udaka, T., Kosaki, R., Matsumoto, M., Ibe, S., Isobe, T., Tanaka, Y., and Takahashi, T. (2006) Molecular Pathology of Shprintzen-Goldberg Syndrome. Am J Med Genet A. 140, 104-8; author reply 109-10.

  7. Le Goff, C., Mahaut, C., Wang, L. W., Allali, S., Abhyankar, A., Jensen, S., Zylberberg, L., Collod-Beroud, G., Bonnet, D., Alanay, Y., Brady, A. F., Cordier, M. P., Devriendt, K., Genevieve, D., Kiper, P. O., Kitoh, H., Krakow, D., Lynch, S. A., Le Merrer, M., Megarbane, A., Mortier, G., Odent, S., Polak, M., Rohrbach, M., Sillence, D., Stolte-Dijkstra, I., Superti-Furga, A., Rimoin, D. L., Topouchian, V., Unger, S., Zabel, B., Bole-Feysot, C., Nitschke, P., Handford, P., Casanova, J. L., Boileau, C., Apte, S. S., Munnich, A., and Cormier-Daire, V. (2011) Mutations in the TGFbeta Binding-Protein-Like Domain 5 of FBN1 are Responsible for Acromicric and Geleophysic Dysplasias. Am J Hum Genet. 89, 7-14.

  8. Faivre, L., Collod-Beroud, G., Loeys, B. L., Child, A., Binquet, C., Gautier, E., Callewaert, B., Arbustini, E., Mayer, K., Arslan-Kirchner, M., Kiotsekoglou, A., Comeglio, P., Marziliano, N., Dietz, H. C., Halliday, D., Beroud, C., Bonithon-Kopp, C., Claustres, M., Muti, C., Plauchu, H., Robinson, P. N., Ades, L. C., Biggin, A., Benetts, B., Brett, M., Holman, K. J., De Backer, J., Coucke, P., Francke, U., De Paepe, A., Jondeau, G., and Boileau, C. (2007) Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome Or Related Phenotypes and FBN1 Mutations: An International Study. Am J Hum Genet. 81, 454-466.

  9. Hilhorst-Hofstee, Y., Hamel, B. C., Verheij, J. B., Rijlaarsdam, M. E., Mancini, G. M., Cobben, J. M., Giroth, C., Ruivenkamp, C. A., Hansson, K. B., Timmermans, J., Moll, H. A., Breuning, M. H., and Pals, G. (2011) The Clinical Spectrum of Complete FBN1 Allele Deletions. Eur J Hum Genet. 19, 247-252.

  10. De Paepe, A., Devereux, R. B., Dietz, H. C., Hennekam, R. C., and Pyeritz, R. E. (1996) Revised Diagnostic Criteria for the Marfan Syndrome. Am J Med Genet. 62, 417-426.

  11. Attanasio, M., Lapini, I., Evangelisti, L., Lucarini, L., Giusti, B., Porciani, M., Fattori, R., Anichini, C., Abbate, R., Gensini, G., and Pepe, G. (2008) FBN1 Mutation Screening of Patients with Marfan Syndrome and Related Disorders: Detection of 46 Novel FBN1 Mutations. Clin Genet. 74, 39-46.

  12. Robinson, P. N., Booms, P., Katzke, S., Ladewig, M., Neumann, L., Palz, M., Pregla, R., Tiecke, F., and Rosenberg, T. (2002) Mutations of FBN1 and Genotype-Phenotype Correlations in Marfan Syndrome and Related Fibrillinopathies. Hum Mutat. 20, 153-161.

  13. Loeys, B. L., Gerber, E. E., Riegert-Johnson, D., Iqbal, S., Whiteman, P., McConnell, V., Chillakuri, C. R., Macaya, D., Coucke, P. J., De Paepe, A., Judge, D. P., Wigley, F., Davis, E. C., Mardon, H. J., Handford, P., Keene, D. R., Sakai, L. Y., and Dietz, H. C. (2010) Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome. Sci Transl Med. 2, 23ra20.

  14. Schrijver, I., Liu, W., Odom, R., Brenn, T., Oefner, P., Furthmayr, H., and Francke, U. (2002) Premature Termination Mutations in FBN1: Distinct Effects on Differential Allelic Expression and on Protein and Clinical Phenotypes. Am J Hum Genet. 71, 223-237.

  15. Rommel, K., Karck, M., Haverich, A., von Kodolitsch, Y., Rybczynski, M., Muller, G., Singh, K. K., Schmidtke, J., and Arslan-Kirchner, M. (2005) Identification of 29 Novel and Nine Recurrent Fibrillin-1 (FBN1) Mutations and Genotype-Phenotype Correlations in 76 Patients with Marfan Syndrome. Hum Mutat. 26, 529-539.

  16. Faivre, L., Collod-Beroud, G., Callewaert, B., Child, A., Binquet, C., Gautier, E., Loeys, B. L., Arbustini, E., Mayer, K., Arslan-Kirchner, M., Stheneur, C., Kiotsekoglou, A., Comeglio, P., Marziliano, N., Wolf, J. E., Bouchot, O., Khau-Van-Kien, P., Beroud, C., Claustres, M., Bonithon-Kopp, C., Robinson, P. N., Ades, L., De Backer, J., Coucke, P., Francke, U., De Paepe, A., Jondeau, G., and Boileau, C. (2009) Clinical and Mutation-Type Analysis from an International Series of 198 Probands with a Pathogenic FBN1 Exons 24-32 Mutation. Eur J Hum Genet. 17, 491-501.

  17. Stheneur, C., Collod-Beroud, G., Faivre, L., Buyck, J. F., Gouya, L., Le Parc, J. M., Moura, B., Muti, C., Grandchamp, B., Sultan, G., Claustres, M., Aegerter, P., Chevallier, B., Jondeau, G., and Boileau, C. (2009) Identification of the Minimal Combination of Clinical Features in Probands for Efficient Mutation Detection in the FBN1 Gene. Eur J Hum Genet. 17, 1121-1128.

  18. Dietz, H. C., McIntosh, I., Sakai, L. Y., Corson, G. M., Chalberg, S. C., Pyeritz, R. E., and Francomano, C. A. (1993) Four Novel FBN1 Mutations: Significance for Mutant Transcript Level and EGF-Like Domain Calcium Binding in the Pathogenesis of Marfan Syndrome. Genomics. 17, 468-475.

  19. Faivre, L., Gorlin, R. J., Wirtz, M. K., Godfrey, M., Dagoneau, N., Samples, J. R., Le Merrer, M., Collod-Beroud, G., Boileau, C., Munnich, A., and Cormier-Daire, V. (2003) In Frame Fibrillin-1 Gene Deletion in Autosomal Dominant Weill-Marchesani Syndrome. J Med Genet. 40, 34-36.

  20. Pereira, L., Andrikopoulos, K., Tian, J., Lee, S. Y., Keene, D. R., Ono, R., Reinhardt, D. P., Sakai, L. Y., Biery, N. J., Bunton, T., Dietz, H. C., and Ramirez, F. (1997) Targetting of the Gene Encoding Fibrillin-1 Recapitulates the Vascular Aspect of Marfan Syndrome. Nat Genet. 17, 218-222.

  21. Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y., and Dietz, H. C. (2003) Dysregulation of TGF-Beta Activation Contributes to Pathogenesis in Marfan Syndrome. Nat Genet. 33, 407-411.

  22. Neptune, E. R., Podowski, M., Calvi, C., Cho, J. H., Garcia, J. G., Tuder, R., Linnoila, R. I., Tsai, M. J., and Dietz, H. C. (2008) Targeted Disruption of NeuroD, a Proneural Basic Helix-Loop-Helix Factor, Impairs Distal Lung Formation and Neuroendocrine Morphology in the Neonatal Lung. J Biol Chem. 283, 21160-21169.

  23. Lima, B. L., Santos, E. J., Fernandes, G. R., Merkel, C., Mello, M. R., Gomes, J. P., Soukoyan, M., Kerkis, A., Massironi, S. M., Visintin, J. A., and Pereira, L. V. (2010) A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and overall Levels of Fbn1 Expression. PLoS One. 5, e14136.