HGNC Approved Gene Symbol: FBN2
SNOMEDCT: 205821003;
Cytogenetic location: 5q23.3 Genomic coordinates (GRCh38) : 5:128,257,909-128,538,245 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q23.3 | Contractural arachnodactyly, congenital | 121050 | Autosomal dominant | 3 |
| Macular degeneration, early-onset | 616118 | Autosomal dominant | 3 |
While investigating the role of fibrillin-1 gene (FBN1; 134797) in the etiology of Marfan syndrome (154700), Lee et al. (1991) isolated a partial cDNA for fibrillin-2.
Using the partial FBN2 cDNA isolated by Lee et al. (1991) to screen an MG-63 human osteosarcoma cell line cDNA library, Zhang et al. (1994) obtained a full-length FBN2 clone. The deduced 2,889-amino acid protein contains an N-terminal signal peptide, followed by a proline-rich region, 3 tandem N-terminal EGF (131530)-like repeats, and 41 calcium-binding EGF-like repeats interspersed with another EGF-like repeat, a glycine-rich region, 7 TGF (see 190180)-binding protein repeats, and 2 Fib motifs. FBN2 also has 2 potential cell attachment sequences, multiple N-glycosylation sites, and 2 C-terminal polylysine stretches. The structures of FBN2 and FBN1 are highly similar, with the most significant difference being the glycine-rich sequence near the N terminus of FBN2, where FBN1 has a proline-rich sequence. FBN2 also contains 2 RGD motifs, whereas FBN1 has only 1. Northern blot analysis detected a 10- to 11-kb FBN2 transcript in MG-63 cells. Western blot analysis detected FBN2 at an apparent molecular mass of 350 kD. Immunohistochemical analysis of human fetal tissues showed colocalization of FBN1 with FBN2 in elastic and nonelastic connective tissues, with preferential accumulation of FBN2 in elastic fiber-rich matrices.
Zhang et al. (1995) cloned mouse Fbn2, which encodes a deduced 2,907-amino acid protein that shares 97% identity with human FBN2.
Using immunohistochemical analysis, Quondamatteo et al. (2002) investigated the distribution of FIB1 and FIB2 in human embryonic and early fetal tissues between gestational weeks 5 and 12. Both fibrillins were widely distributed. In most embryonic and early fetal organs, such as skin, lung, heart, aorta, central nervous system anlage, nerves, and ganglia, both fibrillins followed the same temporo-spatial pattern of distribution. However, in kidney, liver, rib anlagen, and notochord, distribution of FIB1 and FIB2 differed.
Ratnapriya et al. (2014) analyzed RNA sequencing (RNA-Seq) expression data from human fetal tissues and observed high levels of FBN2 transcripts in retinal pigment epithelium and choroid but not in retina. Immunostaining in human fetal eyes showed abundant FBN2 in Bruch membrane, choroid, and sclera. Similar FBN2 expression was obtained in the young adult monkey eye, although labeling was less intense. In contrast to human fetal eyes, FBN2 immunostaining was significantly reduced in choroid and sclera of human donors over 75 years of age, and was undetectable in Bruch membrane. Colabeling studies suggested that FBN2 is localized to the central elastin layer of the Bruch membrane.
Lee et al. (1991) mapped the FBN2 gene to chromosome 5q23-q31 by in situ hybridization.
By analysis of mouse/hamster somatic hybrid cell lines, Li et al. (1993) mapped the mouse Fbn2 gene to chromosome 18.
Zhang et al. (1994) demonstrated differences of expression of fibrillin-1 and fibrillin-2 in human ear cartilage. They noted that this may account for the abnormally shaped (i.e., crumpled) auricular helices that are a hallmark of congenital contractural arachnodactyly (CCA, DA9; 121050).
Using in situ hybridization and immunohistochemical analysis, Zhang et al. (1995) showed that Fib1 and Fib2 were differentially expressed in a temporal and spatial manner during mouse and rat development. In the majority of cases, Fib2 transcripts appeared earlier and accumulated for a shorter period of time than Fib1 transcripts. Synthesis of Fib1 correlated with late morphogenesis and the appearance of well-defined organ structures. Conversely, Fib2 synthesis coincided with early morphogenesis and the beginning of elastogenesis. Zhang et al. (1995) proposed that FIB1 provides mostly force-bearing structural support, whereas FIB2 predominantly regulates the early process of elastic fiber assembly.
Trask et al. (1999) found that human FIB1 and FIB2 homodimerized via an N-terminal region and that the interaction was stabilized by disulfide bonds. Dimer formation occurred intracellularly, suggesting that the process of fibrillin aggregation initiates early after biosynthesis of the molecules. No heterodimers of FIB1 and FIB2 were observed, suggesting that the pro- and gly-rich domains of FIB1 and FIB2, respectively, determine the specificity of dimer formation.
Lin et al. (2002) showed that the N terminus of human FIB1 could assemble in a linear fashion with the C terminus of another FIB1 molecule to form homotypic FIB1 microfibrils in the presence of calcium. FIB1 could interact similarly with FIB2 to form heterotypic microfibrils, but FIB2 N- and C-terminal constructs showed no significant interaction with one another. In dermal fibroblasts from a 1-year-old donor, both FIB1 and FIB2 were detected in a microfibrillar network. In contrast, osteoblasts from a 42-year-old donor showed a microfibrillar network made up of FIB1 alone. Lin et al. (2002) concluded that FIB1 can form microfibrillar structures in the absence of FIB2, and that FIB2 can occur in microfibrils with FIB1.
Congenital Contractural Arachnodactyly
Putnam and Milewicz (1995) and Wang et al. (1995) identified heterozygous point mutations in the FBN2 gene in cases of congenital contractural arachnodactyly (CCA; 121050). A mutation in a calcium-binding EGF-like motif (612570.0001) was found by the first authors and a mutation in a TGF-binding protein-like motif (612570.0002) by the second group.
In 2 patients with CCA, Putnam et al. (1995) identified 2 heterozygous missense mutations in FBN2 that caused substitutions of distinct cysteine residues in separate EGF-like repeats. In addition, Putnam et al. (1995) identified a G-to-A transition at nucleotide 2890 resulting in a val-to-ile change at amino acid 964 (V964I). They found the V964I change to be a common polymorphism with a heterozygosity index of 0.3.
Early-Onset Macular Degeneration
In a father and 4 sons with early-onset macular degeneration (EOMD; 616118), Ratnapriya et al. (2014) identified heterozygosity for a missense mutation in the FBN2 gene (E1144K; 612570.0011). Analysis of 96 additional patients with EOMD as well as 96 patients with age-related macular degeneration (ARMD; see 603075) revealed 2 nonsynonymous rare variants, one in an EOMD patient (M1247T; 612570.0012) and another in a patient with ARMD. Ratnapriya et al. (2014) also detected suggestive association of a common FBN2 nonsynonymous variant (V965I; rs154001) with ARMD (odds ratio, 1.10; p = 3.79 x 10(-5)). The authors concluded that rare and common variants in FBN2 contribute to both mendelian and complex forms of macular degeneration.
In a patient with congenital contractural arachnodactyly (CCA; 121050), Putnam and Milewicz (1995) found a heterozygous G-to-A transition at nucleotide 3755 of their FBN2 cDNA that changed the cysteine at residue 1252 to a tyrosine (C1252Y). This altered one of the highly conserved cysteines in an epidermal growth factor-like domain of the fibrillin-2 protein. By analogy, many of the missense mutations found in FBN1 that result in the Marfan syndrome affect conserved cysteines in the EGF-like domains of the fibrillin-1 protein. The C1252Y mutation altered a restriction enzyme recognition sequence which they used to screen unrelated individuals for the nucleotide substitution; 106 chromosomes failed to show the alteration.
By SSCP analysis followed by direct sequencing, Putnam et al. (1995) identified the C1252Y mutation in 1 of 11 unrelated CCA patients. The mutation was absent in 43 unrelated control individuals and in the other 10 patients.
In a patient with congenital contractural arachnodactyly (CCA; 121050), Wang et al. (1995) found a heterozygous G-to-A transition causing an E390K substitution in a transforming growth factor binding protein-like repeat. This domain is equivalent to exon 9 in the B region of FBN1. This position, in both FBN1 and FBN2, is normally occupied by a negatively charged acidic amino acid, aspartic acid, and glutamic acid, respectively. The authors speculated that the substitution of a glutamic acid by a basic and positively charged lysine could significantly alter the structure of the domain and affect higher order microfibrillar structure.
Wang et al. (1996) described a mother and daughter with classic and severe lethal congenital contractural arachnodactyly (CCA; 121050), respectively. The FBN2 mutation resulted in the identical missplicing of exon 34 in both patients. Significantly, the mother was somatic mosaic for the mutation, thus explaining her milder phenotype. The mutation consisted of an A-to-T transversion at the -2 position of the consensus acceptor splice site, changing AG to TG at the 3-prime end of intron 33. The mother had been born with congenital contractures of the hands, elbows, and knees. Elbow and knee contractures improved spontaneously, and in childhood she underwent surgical release of finger contractures. In adolescence, mitral valve prolapse was recognized. At the age of 24 years, she delivered a premature daughter who was recognized as having CCA on the first day of life. Pregnancy was complicated by a third-trimester polyhydramnios and spontaneous delivery at 34 weeks of gestation. She was diagnosed with type-B interrupted aortic arch with large ventricular septal defect and moderate atrial septal defect, duodenal atresia and intestinal malrotation, single umbilical artery, vertebral anomalies, and arachnodactyly with contractures of elbows and knees. Both ears showed a crumpled irregular superior helix and prominent antihelix and root of the helix. There was pectus excavatum. Duodenal atresia was repaired on day 3, interrupted aortic arch was repaired at 1 month of age, and gastrostomy tube was placed for gastroesophageal reflux requiring subsequent jejunostomy because of gastric perforation, at the age of 1.5 months. The infant experienced multiple episodes of sepsis and died at the age of 9 months.
In a clinically unaffected man with 2 children with congenital contractural arachnodactyly (CCA; 121050), Putnam et al. (1997) found mosaicism for a heterozygous exon splicing error deleting nucleotides 3722 to 3844 of the FBN2 mRNA. This cDNA deletion resulted in selective removal of 1 of the 43 calcium-binding EGF-like domains of the fibrillin-2 protein. Analysis of genomic DNA indicated that the splicing error resulted from an A-to-G transition 15 nucleotides upstream from 3-prime splice site of the intron. The genomic mutation resulting in the splicing error altered a putative branch point sequence important for lariat formation, an intermediate structure of normal splicing. The mutation was detectable in DNA from the father's hair bulbs and buccal cells but not his white blood cell DNA, indicating that the father was a somatic mosaic. Analysis of transcript levels by use of dermal fibroblasts from the proband demonstrated that the FBN2 allele containing the exon deletion was expressed at a higher level than the allele inherited from the mother.
In a 5-generation family in which 18 individuals had congenital contractural arachnodactyly (CCA; 121050), Maslen et al. (1997) found partial skipping of exon 31 of the FBN2 gene in affected individuals. Approximately 25% mutant transcript was produced, which was apparently sufficient to cause a CCA phenotype. Sequence analysis of genomic DNA revealed an unusual base composition for intron 30 and identified a t-to-g transversion at position -26, in the vicinity of the splicing branch-point site in intron 30. This was the first report of a CCA mutation in a multiplex family, unequivocally establishing that mutations in FBN2 are responsible for the CCA phenotype. Branch-point mutations had only rarely been associated with human disease (e.g., 600509.0005). Maslen et al. (1997) pointed out that deletion in exon 31 of the FBN1 gene results in the severe neonatal Marfan syndrome (134797.0019) and a recurrent missplicing of exon 32 (134797.0020) has been observed in 2 unrelated cases of neonatal Marfan syndrome (Wang et al., 1995). It is of note, therefore, that deletion of a corresponding exon in FBN2 is associated with a mild phenotype. The family studied by Maslen et al. (1997) lived in Switzerland. Affected individuals could be identified immediately by their mothers at birth, on the basis of the hands, which were in a clenched (fist-like) position, and on the basis of their ears, which unequivocally were described as resembling 'cabbage leaves.' The auricular deformity resolved with age and was inconspicuous in all affected adults. Camptodactyly also improved with age, but remained the leading phenotypic feature. Contractures of larger joints were present in varying degrees in all affected individuals. Furthermore, all showed kyphoscoliosis, thoracic deformities, and muscular hypoplasia of calves and forearms. All affected individuals had dolichostenomelia and arachnodactyly. In most, arm span significantly exceeded body height but the discrepancy was underestimated because of contractures of elbows and fingers. This same underestimation occurred in assessment of the lower-body segment, as a result of contractures of the knees. Marked truncal adiposity was present in affected females, which contrasted with the long and slender limbs. Two patients, related as first cousins, had undergone surgery for habitual patella luxation and another affected member was observed to have elevated and hypermobile patellas. Most of the affected family members were noted to have fine and thin skin, and supragluteal striae were noted in 3 patients. No cardiovascular abnormalities were detected in any of the affected family members and there was no history or sign of lens dislocation or retinal detachment. A phenotypically particularly instructive pair of dizygotic male twins were pictured. In contrast to the unaffected twin, dolichostenomelia, arachnodactyly, pectus carinatum, hypoplastic calf muscles, elevation of the patella, and a characteristic deformity of the ear were evident.
In a family in which members over 4 generations had signs and symptoms associated with congenital contractural arachnodactyly (CCA; 121050), Babcock et al. (1998) identified a heterozygous G-to-C transversion at nucleotide 3340 of the FBN2 gene. The 3340G-C mutation predicted an asp1114-to-his substitution and also altered the 5-prime donor splice site consensus sequence of exon 25. RT-PCR and DNA sequence analyses demonstrated that this missense mutation also caused low level in-frame missplicing of exon 25 with partial skipping of that exon. Consequently, this single point mutation produced a heterogeneous population of mutant fibrillin-2 molecules in a single individual. Despite the complex manifestation of the mutation, it was associated with a relatively mild phenotype. Analysis of FBN2 allele expression in cultured dermal fibroblasts derived from the proband showed that the mutant allele was preferentially expressed, contributing about 84% of the total transcript. This indicates that an overabundance of mutant transcript does not necessarily correlate with a more severe CCA phenotype. The proband was a 67-year-old woman who was 168 cm tall. Pertinent history included bilaterally dislocating patellae during childhood, chronic aches and pains in numerous joints, muscles, and tendons, and tight hamstrings throughout life. Physical examination showed dental crowding, positive wrist sign of Marfan syndrome, mild thoracic scoliosis, long halluces, tight finger joints, straight elbows, genu valgum, and underdeveloped calf muscles. The external ears were abnormal with an extra piece of cartilage present. Eye findings included myopia and astigmatism. Three daughters were similarly affected. The 39-year-old daughter was 168 cm tall and a had a history of orthopedic problems since birth, including hyperextended feet at birth, contractures of elbows, limited movement in hips, dislocated patellae treated surgically, slight scoliosis, and metatarsus varus. She also had stretch marks on her thighs and an extra piece of cartilage in the external ears. Eye findings included myopia with astigmatism. The 5-year-old son of this woman was thin and tall and had metatarsus varus, contractures of the knees, and the same external ear abnormality. The 37-year-old daughter of the proband was 170 cm tall. She had a history of scoliosis and spinal fusion surgery at age 12 years, dislocated patellae treated surgically, metatarsus varus, thin legs, and contractures of the elbows. On examination, positive thumb sign, positive wrist sign, and long halluces were also noted. She had the same unusual external ears and myopia with astigmatism as did her mother and sister. The 35-year-old daughter of the proband was 173 cm tall and had a history of metatarsus varus, contractures of the elbows, limited hip rotation, and mild myopia. No affected members of this family had abnormal cardiovascular findings.
In a French Canadian girl with typical features of congenital contractural arachnodactyly (CCA; 121050), Belleh et al. (2000) identified a heterozygous 3422G-T transversion in exon 26 of the FBN2 gene, resulting in a cys1141-to-phe (C1141F) amino acid substitution. Neither parent carried the mutation. The pinnae were 'crumpled,' and there was midthoracic kyphoscoliosis. There was restriction to the extension of the thumbs at the metacarpophalangeal joint. The extension at the distal interphalangeal joints of the first to fourth fingers was also limited bilaterally.
Belleh et al. (2000) described a teenaged girl with features of congenital contractural arachnodactyly (CCA; 121050): tall stature, slender body habitus, arachnodactyly, camptodactyly, and progressive kyphoscoliosis. She had mild mental retardation and mild spasticity. Contractures of the fingers were present. As in the other patient reported by Belleh et al. (2000) (see 612570.0008), the legs were slender with reduced muscle mass, particularly in the calves. Belleh et al. (2000) identified a heterozygous 3756T-G transversion in exon 29 of the FBN2 gene, resulting in a cys1252-to-trp (C1252W) substitution.
In a boy with congenital contractural arachnodactyly (CCA; 121050), Sampson et al. (2010) identified a heterozygous 3777T-A transversion in the FBN2 gene, resulting in an asn1259-to-lys (N1259K) substitution in a conserved residue in the calcium-binding EGF-like domain 15. He had congenital contractures of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints of the fingers and toes, contractures of the elbows, mild crumpling of the ear helices without ear pits or tags, and right intraabdominal testis. The patient's father, paternal grandmother, and a paternal cousin were reported to have contractures, but DNA samples from these individuals were not available. In addition to congenital contractures, the patient was also found to have short-segment Hirschsprung disease, pervasive developmental disorder, auditory processing difficulties, and attention deficit-hyperactivity disorder. Genomewide SNP array identified an extended 1.7-Mb deletion at chromosome 16p11.2 (see 613444), which the authors postulated was related to the gastrointestinal abnormality.
In a father and 4 sons with early-onset macular degeneration (EOMD; 616118), Ratnapriya et al. (2014) identified heterozygosity for a c.3430G-A transition in the FBN2 gene, resulting in a glu1144-to-lys (E1144K) substitution within the twelfth Ca(2+)-EGF-like domain. The mutation was not found in an unaffected daughter and son.
In a patient with early-onset macular degeneration (EOMD; 616118), Ratnapriya et al. (2014) identified heterozygosity for a c.3740T-C transition in the FBN2 gene, resulting in a met1247-to-thr (M1247T) substitution within the fifteenth Ca(2+)-EGF-like domain. The variant was not present in 4,300 exomes in the NHLBI Exome Variant Server database.
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Putnam, E. A., Milewicz, D. M. A mutation in the FBN2 gene in dermal fibroblasts from a congenital contractural arachnodactyly patient. (Abstract) Am. J. Hum. Genet. 57: A225, 1995.
Putnam, E. A., Park, E.-S., Aalfs, C. M., Hennekam, R. C. M., Milewicz, D. M. Parental somatic and germ-line mosaicism for a FBN2 mutation and analysis of FBN2 transcript levels in dermal fibroblasts. Am. J. Hum. Genet. 60: 818-827, 1997. [PubMed: 9106527]
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