Species: human
Mutation name:
type: naturally occurring
fertility: unknown
Comment: Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Ratnapriya R et al. (2014) Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. Sengle G et al. (2015) Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Fibrillins 1 and 2 perform partially overlapping functions during aortic development. Carta L et al. (2006) Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Fbn1-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. Analysis of the neonatal Fbn1-/- aorta documented a disorganized and poorly developed medial layer but normal levels of elastin cross-links. Transcriptional profiling revealed that aneurysm progression in Fbn1 null mice is accompanied by unproductive up-regulation of gene products normally involved in tissue repair and vascular integrity, such as plasminogen activator inhibitor-1, activin A, and cysteine-rich angiogenic protein 61. In contrast to Fbn1-/- mice, Fbn2 null mice had a well developed and morphologically normal aortic wall. However, virtually all Fbn1-/-;Fbn2-/- embryos and about half of the Fbn1+/-;Fbn2-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1-/- mice. Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures. Collectively, these data demonstrate that involvement of fibrillin-2 in the initial assembly of the aortic matrix overlaps in part with fibrillin-1 and that continued fibrillin-1 deposition is absolutely required for the maturation and function of the vessel during neonatal life.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Ocular phenotype of Fbn2-null mice. Shi Y et al. (2013) Fibrillin-2 (Fbn2) is the dominant fibrillin isoform expressed during development of the mouse eye. To test its role in morphogenesis, we examined the ocular phenotype of Fbn2(-/-) mice. Ocular morphology was assessed by confocal microscopy using antibodies against microfibril components. Fbn2(-/-) mice had a high incidence of anterior segment dysgenesis. The iris was the most commonly affected tissue. Complete iridal coloboma was present in 37% of eyes. Dyscoria, corectopia and pseudopolycoria were also common (43% combined incidence). In wild-type (WT) mice, fibrillin-2-rich microfibrils are prominent in the pupillary membrane (PM) during development. In Fbn2-null mice, the absence of Fbn2 was partially compensated for by increased expression of fibrillin-1, although the resulting PM microfibrils were disorganized, compared with WTs. In colobomatous adult Fbn2(-/-) eyes, the PM failed to regress normally, especially beneath the notched region of the iris. Segments of the ciliary body were hypoplastic, and zonular fibers, although relatively plentiful, were unevenly distributed around the lens equator. In regions where the zonular fibers were particularly disturbed, the synchronous differentiation of the underlying lens fiber cells was affected. Fbn2 has an indispensable role in ocular morphogenesis in mice. The high incidence of iris coloboma in Fbn2-null animals implies a previously unsuspected role in optic fissure closure. The observation that fiber cell differentiation was disturbed in Fbn2(-/-) mice raises the possibility that the attachment of zonular fibers to the lens surface may help specify the equatorial margin of the lens epithelium.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: None
Comment: Two novel fibrillin-2 mutations in congenital contractural arachnodactyly. Belleh S et al. (2000) Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin-2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin-2 region homologous to the so-called neonatal Marfan syndrome region of fibrillin-1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3' UTR polymorphism is also described.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. Maslen C et al. (1997) Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically similar to but genetically distinct from Marfan syndrome. Genetic-linkage analysis has implicated the fibrillin-2 gene (FBN2) as the CCA locus. Mutation analysis of two isolated CCA patients revealed missense mutations, indicating that defects in FBN2 may be responsible for this disorder. However, cosegregation of a mutant allele with the disease phenotype has not yet been established. We have investigated the primary cause of CCA in a large well-characterized kindred with five generations comprising 18 affected individuals. Previous studies demonstrated linkage of this family's CCA phenotype to FBN2. Mutation analysis of cDNA derived from the proband and her affected brother, using a nonisotopic RNase cleavage assay, revealed the partial skipping of exon 31. Approximately 25% mutant transcript is produced, which is apparently sufficient to cause a CCA phenotype. Sequence analysis of genomic DNA revealed an unusual base composition for intron 30 and identified the mutation, a g-26t transversion, in the vicinity of the splicing branch-point site in intron 30. Genomic DNA from 30 additional family members, both affected and unaffected, then was analyzed for the mutation. The results clearly demonstrate cosegregation of the branch-point mutation with the CCA phenotype. This is the first report of a CCA mutation in a multiplex family, unequivocally establishing that mutation in FBN2 are responsible for the CCA phenotype. In addition, branch-point mutations only very rarely have been associated with human disease, suggesting that the unusual composition of this intron influences splicing stability.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Chaudhry SS et al. (2001) Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres. MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures. Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS. All the mutations described in CCA occur in the "neonatal region" of FBN2. Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the "neonatal region" of Fbn2 cause syndactyly in mice. These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the "neonatal region" of FBN2.//////////////////