Fibrillin mutations in Marfan syndrome and related phenotypes

Current Opinion in Genetics and Development

Volumn 6, Issue 3, 1996, Pages 309-315

  Ramirez, Francesco ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FIBRILLIN; ACTIN BINDING PROTEIN;

ARACHNODACTYLY; DNA POLYMORPHISM; EXON; FIBER; GENE EXPRESSION; GENE MUTATION; GENETIC LINKAGE; INTRON; MARFAN SYNDROME; PHENOTYPE; POLYMERIZATION; PRIORITY JOURNAL; REVIEW; ANIMAL; GENETICS; HUMAN; METABOLISM; MUSCLE CELL; MUTATION;

ANIMALS; HUMANS; MARFAN SYNDROME; MICROFILAMENT PROTEINS; MUSCLE FIBERS; MUTATION; PHENOTYPE;

EID: 0029665565     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(96)80007-4     Document Type: Article

References (56)

1. Dietz H, Ramirez F, Sakai L: Marfan syndrome and other microfibrillar diseases. In Advances in Human Genetics, vol 22. Edited by Harris H, Hirschhorn K. New York: Plenum Press; 1994:153-186.
2. Dietz H, Pyeritz R: Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 1995, 4:1799-1809. An excellent and detailed account of fibrillin mutations with an exhaustive bibliography and a balanced discussion of the postulated consequences of the major classes of defects.
3. Beighton P, De Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick VA et al.: International nosology of heritable disorders of connective tissue. Am J Med Genet 1988, 29:581-594.
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5. Dietz H, Cutting G, Pyeritz R, Maslen C, Sakai L, Corson G, Puffenberger E, Hamosh A, Nanthakumar E, Curristin S et al.: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991, 352:337-339.
6. Collod G, Beroud C, Soussi T, Junien C, Boileau C: Software and database for the analysis of mutations in the human FBN1 gene. Nucleic Acids Res 1995, 24:137-141.
7. 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, 57:8-21. The article documents the usefulness of a new strategy designed to identify structural and splicing mutations by selective screening of the 110kb amplicon of the FBN1 gene. The report details the optimal conditions of PCR amplification for each set of primers. It also reports a few new MFS mutations.
8. Pereira L, Levran O, Ramirez F, Lynch J, Sykes B, Pyeritz RE, Dietz H: A molecular approach to the stratification of cardiovascular risk in families with Marfan syndrome. N Engl J Med 1994, 331:148-153. This is the first instance in which haplotype segregation analysis has been employed in FBN1 linkage studies. The authors discuss its application to prenatal and presymptomatic diagnosis of the disorder. They also show data suggesting that, in some families, distinct MFS manifestations may be caused by genes other than FBN1.
9. Boileau C, Jondeau G, Baron MC, Coulon M, Alexandre JA, Sakai L, Melki J, Delorme G, Dubourg O, Bonaiti-Pellie C et al.: Autosomal dominant Marfan-like connective tissue disorder with aortic dilation and skeletal abnormalities not linked to the fibrillin genes. Am J Hum Genet 1993, 53:46-54.
10. Collod G, Babron MC, Jondeau G, Coulon M, Weissenbach J, Duborg O, Bourdarias JP, Bonaiti-Pellie D, Junien C, Boileau C: A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet 1994, 8:264-268. This is the only report to date of an MFS family unlinked to either of the fibrillin genes. This finding raises two possibilities. The first is that MFS could also be caused by a gene encoding another microfibrillar component. Recent evidence indicates that fibulin 2 - a microfibril-associated component the corresponding locus of which is on chromosome 3 (LY Sakai, personal communication) - is not such a gene (G Collod et al., abstract 1211, 45th Annual Meeting of the American Society of Human Genetics, Minneapolis, October 1995). The second possibility is that dysfunction of a non matrix related gene product could be the cause of this (then misdiagnosed) MFS phenotype. The dispute surrounding the MFS diagnosis of this French family is addressed further in the following epistles [11-15].
11. Collod G, Babron MC, Jondeau G, Coulon M, Weissenbach J, Duborg O, Bourdarias JP, Bonaiti-Pellie D, Junien C, Boileau C: A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet 1994, 8:264-268. This is the only report to date of an MFS family unlinked to either of the fibrillin genes. This finding raises two possibilities. The first is that MFS could also be caused by a gene encoding another microfibrillar component. Recent evidence indicates that fibulin 2 - a microfibril-associated component the corresponding locus of which is on chromosome 3 (LY Sakai, personal communication) - is not such a gene (G Collod et al., abstract 1211, 45th Annual Meeting of the American Society of Human Genetics, Minneapolis, October 1995). The second possibility is that dysfunction of a non matrix related gene product could be the cause of this (then misdiagnosed) MFS phenotype. The dispute surrounding the MFS diagnosis of this French family is addressed further in the following epistles [11-15].
12. Gilchrist DM: Marfan syndrome or Marfan-like connective tissue disorder [Letter]. Am J Hum Genet 1994, 54:553.
13. Boileau C, Jondeau G, Bourdarias JP, Junien C: Marfan syndrome or Marfan-like connective tissue disorder [Reply]. Am J Hum Genet 1994, 54:544.
14. Byers PH; Marfan syndrome or Marfan-like connective tissue disorder [Editor's note]. Am J Hum Genet 1994, 54:553-554.
15. Dietz H, Francke U, Furthmayr H, Francomano C, DePaepe A, Devereux R, Ramirez F, Pyeritz R: The question of heterogeneity in Marfan syndrome [Letter]. Nat Genet 1995, 9:228-229.
16. Boileau C, Junien C, Collod G, Jondeau G, Dubourg O, Bourdarias JP, Bonaiti-Pellie C, Frezal, Maroleaux P: The question of heterogeneity in Marfan syndrome [Reply]. Nat Genet 1995, 9:230-231.
17. Hayward C, Porteous MEM, Brock D: A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mol Cell Probes 1994, 8:325-327.
18. 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, 95:2372-2378. This contribution provides good genetic evidence for profibrillin processing. Pulse-chase analysis of cultured fibroblasts from an individual with a missense mutation shows an accumulation of larger and normal-size fibrillin molecules in the culture media. The biosynthetic data indicate that, unlike the latter, the larger product is apparently not incorporated into the matrix fraction. Assuming that the conclusion is correct, this represents the first and only case of an abnormality associated with fibrillin 1 haploinsufficiency. An additional implication of the study is the possible existence of a novel furin/PACE activity in mammalian cells.
19. Lönqvist L, Child A, Kainulainen K, Davidson R, Puhakka L, Peltonen L: A novel mutation of the fibrillin gene causing ectopia lentis. Genomics 1994, 19:573-576.
20. Francke U, Berg MA, Tynan K, Brenn T, Liu W, Aoyama T, Gasner C, Miller DC, Furthmayr H: A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection. Am J Hum Genet 1995, 56:1287-1296.
21. 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, 17:468-475.
22. Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC: Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet 1996, 12:209-211. This article presents the first characterization of the genetic lesion in Shprintzen-Goldberg syndrome. As such, it is the first report for fibrillin deficiency associated with severe CNS manifestations and craniosynoslosis. The mutation (Cys1223→Tyr; Fig. 1) is located in the 'neonatal' region of the protein, but in an EGFcb repeat where no other mutations have been found previously. The authors explain the unusual finding by invoking their own recent data [53•], showing PCR-based FBN1 expression in 6-8 cell blastomers. Accordingly, they argue that such a pattern is consistent with a role of fibrillin 1 in early craniofacial and CNS development. Future studies will test the validity of the hypothesis.
23. Viljoen D: Congenital contractual arachnodactyly (Beals syndrome). J Med Genet 1994, 31:640-643. The most recent update describing the clinical features of CCA; this short article gives an idea of CCA variability and an estimate of the degree of overlap with MFS. Clinical features showing variable expression include cranial manifestations, such as micrognatia and highly arched palate, and musculoskeletal anomalies, such as kyphoscoliosis and muscle hypoplasia. A small group of CCA patients exhibit mitral valve prolapse and regurgitation and, more rarely, aortic root dilatation and dislocated lenses. It would be interesting to determine the relationship between these unusual CCA/MFS phenotypes and the fibrillin genes.
24. Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, Tsipouras P, Ramirez F, Hollister DW: Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991, 352:330-334.
25. Putnam EA, Zhang H, Ramirez F, Milewicz DM: Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 1995, 11:456-458. Provides final and rigorous proof for early linkage data [23] that suggested a cause/effect relationship between CCA and fibrillin 2 mutations. Interestingly, the missense mutations of this rather mild phenotype occur in the fibrillin 2 counterpart of the so-called 'neonatal' region of fibrillin 1 [7•,32••,33,34]. Several other fibrillin 2 mutations have been subsequently identified in CCA patients; they include mis-splicing of exons 29 and 34, and a missense mutation in exon 25 (D Milewicz, personal communication; M Godfrey, personal communication). The first two are both cases of somatic mosaicism, whereas the third mutation gives rise to a new amino-glycosylation site.
26. Zhang H, Apfelroth SD, Hu W, Davis EC, Sanguineti C, Bonadio J, Mecham RP, Ramirez F: Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices. J Cell Biol 1994, 124:855-863. By using a combination of molecular, biochemical, histological and ultrastructural approaches, the authors demonstrate the existence of a second fibrillin protein in extracellular microfibrils. The authors have established that fibrillins are structurally related 350 kDa glyproteins, and that fibrillin 2 accumulates preferentially during embryogenesis and in elastic tissues. This work thus raises the intriguing possibility that morphologically similar microfibrils are actually different in fibrillin composition. The postulate suggests that compositional differences are responsible for tissue specificity, and thus for the morphological/functional variety of microfibrillar aggregates.
27. Zhang H, Hu W, Ramirez F: Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol 1995, 129:1165-1176. Building on the findings of previous work [25••], this study employed in situ hybridization to compare the pattern of expression of fibrillins 1 and 2 during mouse embryogenesis. The results indicate that, in all but one organ system, fibrillin 2 is produced earlier than fibrillin 1 and transiently. (The exception is the cardiovascular system, the pathology of which distinguishes MFS from CCA; here, fibrillin 1 production is consistently and increasingly higher than fibrillin 2.) The authors elaborate on the significance of these findings in relationship to CCA versus MFS and hypothesize on the possible role of each fibrillin.
28. Pereira L, D'Alessio M, Ramirez F, Lynch J, Sykes B, Pangilinan T, Bonadio J: Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum Mol Genet 1993, 2:961-968.
29. Corson G, Chalber SC, Dietz H, Charbonneau NL, Sakai L: Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics 1993, 17:476-484.
30. Tilstra D, Li L, Potter KA, Womack J, Byers PH: Sequence of the coding region of the bovine fibrillin cDNA and localization to bovine chromosome 10. Genomics 1994, 23:480-485.
31. Yin W, Smiley E, Germiller J, Sanguineti C, Lawton T, Pereira L, Ramirez F, Bonadio J: Primary structure and developmental expression of Fbn-1, the mouse fibrillin gene. J Biol Chem 1995, 270:1798-1806.
32. Reber-Müller S, Spissinger T, Schuchert P, Spring J, Schimid V: An extracellular matrix protein of jellyfish homologous to mammalian fibrillins forms different fibrils depending on the life stage of the animal. Dev Biol 1995, 169:662-672. An extremely interesting study which documents, for the first time, the existence of fibrillin and the beads-on-a-string structure in an invertebrate organism. The authors also report changes in matrix organization of the cognate microfibrils during ontogeny and at different developmental stages. This remarkable study therefore implicates fibrillin as a key determinant in metazoan physiology.
33. 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, 6:64-69. A report which, on the basis of three cases, suggested preferential clustering of neonatal lethal mutations in the middle portion of the fibrillin protein. The conclusion was subsequently supported by others [7•,33,34]. The authors note that the mutations reside within the longest stretch of EGFcb repeats which, as previously argued [27], may function as a single unit by forming a common β sheet between contiguous repeals. (To learn more about the ectopia lentis mutation, see the other article in which the defect was reported [18].)
34. Milewicz D, Duvic M: Severe neonatal Marfan syndrome resulting from a de novo 3-bp insertion into the fibrillin gene, on chromosome 15. Am J Hum Genet 1994, 54:447-453.
35. Wang M, Price CE, Han J, Cisler J, Imaizumi K, Van Thienen MN, DePaepe A, Godfrey M: Recurrent mis-splicing of fibrillin exon 32 in two patients with neonatal Marfan syndrome. Hum Mol Genet 1995, 4:607-613.
36. Aoyama T, Francke U, Dietz HC, Furthmayr H: Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms. J Clin Invest 1994, 94:130-137. This study classifies fibrillin 1 defects into distinct biosynthetic groups. Using pulse-chase analysis of cultured fibroblasts, the authors divide 55 samples into the following major classes: groups I and II (49% of samples), with reduced synthesis, normal secretion and normal or decreased extracellular deposition; groups III and IV (44% of cases), with normal synthesis, reduced secretion and different degrees of reduced matrix incorporation; and group V (7% of cases), with no differences from control samples. The authors integrate the data into a general model that explains how the biosynthetic defects are ultimately translated into metabolic deficiencies. The lack of apparent deficiencies in group V was used in [10••] as indirect evidence for MFS heterogeneity.
37. Raghunath M, Kielty CM, Steinmann B: Truncated profibrillin of a Marfan patient is of apparent similar size as fibrillin: intracellular retention leads to over-N-glycosylation. J Mol Biol 1995, 248:901-909. The authors provide supportive evidence for a calcium-dependent endoprotease activity in fibroblasts by relating the rate of profibrillin conversion to EGTA treatment (see [17••]). They also argue very convincingly that not all of the potential amino-glycosylation sites of fibrillin are utilized because brefeldin treatment leads to overmodified chains which tunicamycin treatment converts back to normal. The biosynthetic evidence for polymerization of unprocessed mutant profibrillins is less convincing. In addition, it contradicts the conclusion of Milewicz et al. [17••] that unprocessed chains are excluded from polymerization.
38. McGookey-Milewicz M, Pyeritz RE, Crawford ES, Byers PH: Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 1992, 89:79-86.
39. Aoyama T, Tynan K, Dietz HC, Francke U, Furthmayr H: Missense mutations impair intracellular processing of fibrillin and microfibril assembly in Marfan syndrome. Hum Mol Genet 1993, 12:2135-2140.
40. Sakai L, Keene D, Glanville RW, Bachinger HP: Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J Biol Chem 1991, 22:14763-14770.
41. Barr PJ: Mammalian subtilisins: the long-sought dibasic processing endoproteases. Cell 1991, 66:1-3.
42. Raghunath M, Kielty CM, Kainulainen K, Child A, Peltonen L, Steinmann B: Analyses of truncated fibrillin caused by a 366 bp deletion in the FBN1 gene resulting in Marfan syndrome. Biochem J 1994, 302:889-896.
43. Klimpel KR, Molloy SS, Thomas G, Leppla SH: Anthrax toxin protective antigen is activated by a cell surface protease with the sequence specificity and catalytic properties of furin. Proc Natl Acad Sci USA 1994, 89:10277-10281.
44. Reinhardt DP, Keene DR, Corson GM, Poschl E, Bachinger P, Gambee JE, Sakai LY: Fibrillin 1: organization in microfibrils and structural properties. J Mol Biol 1996, 258:104-116. The authors of this elegant study have produced large fibrillin 1 peptides in cultured cells which together span the entire molecule. They used these reagents to map the epitopes of monoclonal antibodies which were, in turn, employed to establish the organization of fibrillin monomers within the beads-on-a-string structure. Aside from corroborating their previous model [39], the study revealed intracellular carboxy-terminal as well as amino-terminal processing of recombinant peptides. The finding has direct impact on the interpretation of data described in other articles [17••,47].
45. Hayward C, Porteous ME, Brock DJ: Identification of a novel nonsense mutation in the fibrillin gene (FBN1) using nonisotopic techniques. Hum Mutat 1994, 3:159-162.
46. Kainulainen K, Sakai LY, Child A, Pope FM, Puhakka L, Pyhanen L, Palotie A, Kaitila I, Peltonen L: Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides. Proc Natl Acad Sci USA 1992, 89:5917-5921.
47. Eldadah ZA, Brenn T, Furthmayr H, Dietz HC: Expression of a mutant human fibrillin allele upon a normal human or murine genetic background recapitulates a Marfan cellular phenotype. J Clin Invest 1995, 95:874-880. The original aim of the study was to elucidate whether or not the MASS phenotype of a previously described patient [20] is caused by haploinsufficiency or by dominant-negative pathogenesis. The mutation is a complex one that leads to the production of low amounts (6%) of a truncated (55 residue) product. The authors show that transfection of an expression vector, modeled after the defect, disrupts the endogenous microfibrils of normal fibroblasts in the same way as the mutation in the patient's cells. The results imply thai the amino-terminal end of fibrillin participates in polymerization. This conclusion contrasts, however, with the evidence for carboxy-terminal processing [17••], and with the suggestion of amino-terminal processing [43•].
48. Glanville RW, Qian RQ, McClure DW, Maslen CL: Calcium binding, hydroxylation, and glycosylation of the precursor epidermal growth factor-like domains of fibrillin-1, the Marfan gene protein. J Biol Chem 1994, 269:26630-26634.
49. Handford P, Downing AK, Rao Z, Hewett DR, Sykes BC, Kielty CM: The calcium binding properties and molecular organization of epidermal growth factor-like domains in human fibrillin-1. J Biol Chem 1995, 270:6751-6756.
50. Kielty C, Shuttleworth CA: The role of calcium in the organization of fibrillin microfibrils. FEBS Lett 1993, 336:323-326.
51. 2+-binding epidermal growth factor-like domain: its role in protein-protein interactions. Cell 1995, 82:131-141. This elegant study documents the critical role of calcium in folding and stabilizing individual and multiple EGFcb domains. The authors have used high resolution X-ray crystallography to determine the structure of an EGFcb domain and the spatial arrangement of the ligands involved in binding calcium. As a result, they show that calcium forms a seven-ligand pentagonal bipyramid with one ligand mediating intramolecular protein-protein contacts. They also note thai the crystal structure is built from tightly wound helices of EGFcb domains.
52. Kielty CM, Shuttleworth CA: Abnormal fibrillin assembly by dermal fibroblasts from two patients with Marfan syndrome. J Cell Biol 1994, 124:997-1004. The article describes how fibrillin 1 mutations in MFS can be categorized according to ultrastructural features of the resulting protein. To this end, the authors compare microfibrils isolated from post-confluent cell layers from either control of MFS individuals by rotary shadowing electron microscopy. They find gross morphological alterations in a sample from a moderately affected MFS patient with a calcium-binding mutation, and no purifiable microfibrils in a sample from a classic MFS case involving an internally deleted EGFcb domain. Subsequent studies [17••,36•,41,54] have examined other mutations in the same way.
53. Mariencheck MC, Davis EC, Zhang H, Ramirez F, Rosenbloom J, Gibson MA, Parks WC, Mecham RP: Fibrillin-1 and fibrillin-2 show temporal and tissue-specific regulation of expression in developing elastic tissues. Connect Tissue Res 1995, 31:87-97.
54. Eldadah ZA, Grifo JA, Dietz HC: Marfan syndrome as a paradigm for transcript-targeted preimplantation diagnosis of heterozygous mutations. Nat Med 1995, 1:798-803. Employing MFS as a paradigm, this study describes a reliable reverse-transcriplase PCR based method of genotyping single cells from 6-8 cell blastomers. The method has a wide application potentially for pre-implantation diagnosis of heterozygous diseases. Additionally, the study provides evidence for PCR-detectable transcripts of fibrillin 1 at very early stages of human development. The last finding is used by the same authors to explain the phenotypic abnormalities of the Shprintzen-Goldberg syndrome [21•].
55. Kielty CM, Rantamäkit, Child AH, Shuttleworth A, Peltonen L: Cysteine-to-arginine point mutation in a "hybrid" eight-cysteine domain of FBN1: consequences for fibrillin aggregation and microfibril assembly. J Cell Sci 1995, 108:1317-1323.
56. Siracusa LD, McGrath R, Ma Q, Moskow JJ, Manne J, Christner PJ, Buchberg AM, Jimenez SA: A tandem duplication within the fibrillin 1 gene is associated with the mouse Tight skin mutation. Genome Res 1996, in press. This important paper correlates the Tsk chromosome with an in-frame 40 kb intragenic duplication of Fbn1 and with the production of a transcript 3 kb longer than the normal one. Although lacking formal proof, the authors surmise that the complex Tsk phenotype - proportionate bone and cartilage overgrowth, thickened skin, excessive matrix deposition, and scleroderma-like autoimmmune manifestations - may be directly or indirectly caused by abnormal microfibrils that contain both the wild-type and mutant products. Postulating a dominant negative effect for the Fbn1 mutation does not, however, explain the remarkable differences between the Tsk and MFS phenotypes. It is possible that the mutant product exerts a function other than structural (gain of function) or that the duplication affects the expression of surrounding gene(s) (position effect).