Alternative titles; symbols
HGNC Approved Gene Symbol: EFEMP2
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,866,441-65,872,800 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Cutis laxa, autosomal recessive, type IB | 614437 | Autosomal recessive | 3 |
Members of the fibulin family of proteins, like EFEMP2, are extracellular matrix proteins characterized by tandem arrays of EGF (131530)-like domains and a C-terminal fibulin (see FBLN1; 135820)-type module (Kobayashi et al., 2007).
A large number of extracellular matrix proteins contain variations of the EGF domain, e.g., fibrillin (FBN1; 134797) and Notch (190198). As part of their efforts in transcriptional mapping of the human 11q13.1-q13.2 genomic region, Katsanis et al. (2000) identified a novel partial cDNA from a human brain cDNA library. They called the cDNA 'EGF-containing fibulin-like extracellular matrix protein-2' (EFEMP2) because of its significant homology to EFEMP1 (601548). Sequence analysis detected 6 putative calcium-binding EGF domains and 4 EGF modules. Katsanis et al. (2000) observed expression of a 2.0-kb EFEMP2 transcript in all adult tissues tested by Northern blot analysis, with highest levels in heart. RT-PCR detected a 105-bp amplicon from the 3-prime untranslated region in fetal brain, kidney, and heart, but not in lung. EFEMP1 is likewise expressed in a wide range of adult and fetal tissues. In contrast to EFEMP1, however, EFEMP2 was not significantly overexpressed in senescent or quiescent fibroblasts, suggesting a diversity of function within this EGF-like domain subfamily. Katsanis et al. (2000) also cloned the mouse Efemp2 homolog.
Using radioimmunoassays, Kobayashi et al. (2007) found variable Fbln4 expression in all 14 mouse tissues examined, with highest expression in aorta, and lowest expression in heart and thymus. Immunohistochemical analysis localized Fbln4 in perichondrium of developing bone in day-15 mouse embryos and in lung parenchyma in day-14 mouse embryos. Electron microscopy after rotary shadowing revealed that recombinant mouse Fbln4, like Fbln3 (EFEMP1; 601548) and Fbln5 (604580), appeared as a 20-nm rod with a globular domain at one end, which represented the N-terminal EGF modules.
By analysis of a somatic cell hybrid panel and by placement on a series of genomic clones by PCR, Katsanis et al. (2000) mapped the EFEMP2 gene to chromosome 11q13, in an area where several retinopathies have shown genetic linkage.
Kobayashi et al. (2007) found that mouse Fbln3 and Fbln4 and both mouse and human FBLN5 were secreted into the culture media of transfected HEK293 cells. Solid-phase binding assays showed that these proteins bound differentially to extracellular proteins. Mouse Fbln4 bound to collagen XIV (see 120324), nidogen-2 (NID2; 605399), tropoelastin (ELN; 130160), and collagen XV (see 120325)-derived endostatin, but not to fibronectin (135600) or most basement membrane proteins examined.
By immunoprecipitation analysis, Schiavinato et al. (2017) identified fibulin-4 as a direct binding partner of Emilin1 (130660). Further analysis showed that fibulin-4 and Emilin1 colocalized in mouse calvarial bone and that fibulin-4 deposition required Emilin1 in extracellular matrix of osteoblasts.
Doyne Honeycomb Retinal Dystrophy
Given that EFEMP1 is the site of mutations causing Doyne honeycomb retinal dystrophy (126600), Katsanis et al. (2000) suggested EFEMP2 as a candidate for retinal dystrophies. Toto et al. (2002) studied linkage of both the EFEMP2 and EFEMP1 genes to malattia leventinese in a 3-generation Swiss-Italian family. Linkage was found only to EFEMP1 in 2 of 5 affected family members.
Autosomal Recessive Cutis Laxa Type IB
Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. A severe autosomal recessive form of cutis laxa (ARCL1A; 219100) is caused by mutation in the fibulin-5 gene (FBLN5; 604580). Hucthagowder et al. (2006) hypothesized that mutations in other members of the fibulin gene family may cause cutis laxa as well. In a child of Iraqi descent with cutis laxa and severe systemic connective tissue abnormalities (ARCL1B; 614437), Hucthagowder et al. (2006) detected a homozygous missense mutation in the FBLN4 gene (604633.0001). The role of fibulin-4 in elastic fiber formation is evolutionarily conserved in mammals (McLaughlin et al., 2006); however, additional observations in the patient of Hucthagowder et al. (2006) suggested that fibulin-4 may have additional pleiotropic functions in vascular patterning and collagen biosynthesis.
In an infant girl who died at day 27 of life with apparent arachnodactyly, cutis laxa, and severe systemic vascular abnormalities similar to those of the patient described by Hucthagowder et al. (2006), and who was negative for mutation in the FBLN5 gene, Dasouki et al. (2007) identified compound heterozygosity for a missense mutation and a 4-bp duplication in the FBLN4 gene (604633.0002 and 604633.0003, respectively). Dasouki et al. (2007) concluded that deficiency in fibulin-4 leads to a perinatal lethal condition associated with elastic tissue abnormalities.
Hoyer et al. (2009) reported the third case of cutis laxa due to mutation in FBLN4, an infant girl who died immediately after birth with extreme bradycardia and who was found to be homozygous for a missense mutation (604633.0004). Hoyer et al. (2009) stated that this case extended the phenotypic spectrum of FBLN4 mutations to include microcephaly, overgrowth, and arachnodactyly.
Renard et al. (2010) sequenced the FBLN4 gene in 17 patients with prominent cutis laxa but no major cardiovascular findings, and detected no mutations. Analysis of FBLN4 in a second cohort of 22 patients who had mild skin involvement but significant cardiovascular features, including arterial tortuosity, stenosis, and aneurysms, revealed homozygosity or compound heterozygosity for mutations in the FBLN4 gene in 3 patients (604633.0005-604633.0008). Renard et al. (2010) concluded that patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms and arterial tortuosity and stenosis. Immunostaining of aortic and lung tissue showed an increase in TGF-beta (190180), which was confirmed by phosphorylated SMAD2 (601366) immunoblotting of fibroblast cultures; Renard et al. (2010) stated that this was the first evidence of involvement of altered TGFB signaling in the pathogenesis of FBLN4 mutations in humans.
Kappanayil et al. (2012) reported 22 unrelated infants from the Malabar region of the southern Indian state of Kerala. All were Muslims and came from the community known as the Mappilas. Twenty-one of 22 were homozygous for a missense mutation in exon 7 of FBLN4 (604633.0009). One patient was compound heterozygous for this mutation and a second, de novo, mutation (604633.0010) on her paternal chromosome. Both mutations occurred in the same calcium-binding EGF domain of the protein. Neither mutation was found among 200 control alleles.
Horiguchi et al. (2009) found that mice homozygous for conditional knockout of Fbln4 specifically in smooth muscle and mice compound heterozygous for smooth muscle-specific Flbn4 knockout and constitutive Fbln4 knockout had normal growth, fertility, and survival up to 1 year. Arteries of homozygous conditional knockout mice had residual (18.5%) expression of Fbln4, which was sufficient for embryonic development of elastic laminae, but was insufficient to support the development of elastic laminae after birth. Compound heterozygous mice had a greater reduction in Fbln4 expression (8.4%) and were unable to organize elastic laminae in embryogenesis, leading to ascending aortic aneurysm. Moreover, disruption of Fbln4 led to morphologically and physiologically impaired aortic elastic laminae, resulting in significantly stiff aortae. Further analysis revealed that Fbln4 specifically interacted with the propeptide of Lox (153455) through its N-terminal domain and colocalized with Lox on elastic fibers. By interacting with the Lox propeptide, Fbln4 tethered it on tropoelastin, thereby playing a role in elastogenesis.
Papke et al. (2015) found that knockout of Efemp2 targeted to mouse smooth muscle (SMKO) resulted in altered fibrillar collagen localization with larger, profoundly disorganized fibrils. Collagen pro-lysyl oxidase (LOX) activity was reduced in Efemp2-null mouse embryonic fibroblasts, and collagen cross-linking was diminished in SMKO aorta, but elastin cross-linking was unaffected, and the level of mature Lox was maintained to that of wildtype aorta. Proteomic screening identified multiple potential Efemp2 binding partners involved in procollagen processing and maturation. The authors confirmed that Efemp2 bound procollagen C-endopeptise enhancer-1 (PCOLCE; 600270), which enhances proteolytic cleavage of the procollagen C-terminal propeptide. However, procollagen cleavage was not affected by loss of Efemp2. Papke et al. (2015) concluded that EFEMP2 may function as a scaffolding protein during collagen maturation in the extracellular space.
In a child of nonconsanguineous parents of Iraqi descent with cutis laxa (ARCL1B; 614437), Hucthagowder et al. (2006) found homozygosity for a 169G-A transition in the FBLN4 gene that resulted in a glu57-to-lys (E57K) amino acid substitution. Each of her parents was heterozygous for this mutation. Multiple alignments showed that the E57 residue was completely conserved in calcium-binding epidermal growth factor (EGF) modules, consistent with this residue being essential for calcium binding. Hucthagowder et al. (2006) pointed out that the same substitution at a homologous residue in fibulin-1, E1073K (134797.0038), causes severe, neonatal Marfan syndrome.
In an infant girl with cutis laxa, apparent arachnodactyly, and severe systemic vascular abnormalities (ARCL1B; 614437), who died at day 27 of life, Dasouki et al. (2007) identified compound heterozygosity for an 835C-T transition in exon 8 of the EFEMP2 gene, resulting in an arg279-to-cys (R279C) substitution at a highly conserved residue at the end of the fifth cbEGF module, and a 4-bp duplication in exon 10 (1070dupCCGC; 604633.0003), predicted to truncate the protein and replace the last 85 amino acids of the FC domain with an incorrect arg residue. The missense mutation was not found in 50 controls. Analysis of the patient's fibroblasts revealed that fibulin-4 protein was barely detectable in culture medium and not seen in cell extract and matrix, and immunostaining of patient fibroblasts showed a total absence of fibulin-4 fibers from the extracellular matrix.
Renard et al. (2010) performed immunohistochemical staining of fibulin-4 on aortic tissue from the patient previously studied by Dasouki et al. (2007) and confirmed the near absence of extracellular fibulin-4 in the aortic wall compared to the control, whereas intracellular staining was similar to that of the control, suggesting that the mutant protein is either not secreted or is secreted into extracellular space to a lesser extent. Immunohistochemical staining for phosphorylated SMAD2 (601366) and CTGF (121009), an effector of TGF-beta (190180) signaling and a TGF-beta-driven gene product, respectively, in patient aorta and lungs showed a more intense and increased nuclear staining compared to control tissues.
For discussion of the 4-bp duplication in the EFEMP2 gene (1070dupCCGC) that was found in compound heterozygous state in a patient with cutis laxa, apparent arachnodactyly, and severe systemic vascular abnormalities (ARCL1B; 614437) by Dasouki et al. (2007), see 604633.0002.
In an infant girl with cutis laxa (ARCL1B; 614437), born of consanguineous Iraqi parents, Hoyer et al. (2009) identified homozygosity for an 800G-A transition in exon 7 of the FBLN4 gene, resulting in a cys267-to-tyr (C267Y) substitution involving the fifth of six highly conserved residues in the fifth cbEGF module. The unaffected parents were heterozygous for the mutation.
Renard et al. (2010) performed immunoblotting experiments on the culture medium of dermal fibroblasts from the patient previously studied by Hoyer et al. (2009), and observed a complete absence of fibulin-4. Immunoblotting after TGF-beta (TGFB; 190180) stimulation of patient fibroblast cultures indicated a significantly increased phosphorylated SMAD2 (601366) signal compared to controls, suggesting that mutation in FBLN4 has an effect on the TGFB signaling pathway.
In a 20-year-old woman with velvety skin and severe arterial tortuosity, aneurysm, and stenosis (ARCL1B; 614437), originally reported by Ades et al. (1996), Renard et al. (2010) identified homozygosity for a 376G-A transition in exon 5 of the EFEMP2 gene, resulting in a glu126-to-lys (E126K) substitution at an evolutionarily conserved residue in the DINE consensus sequence of the second cbEGF-like domain. The mutation was not found in 200 control chromosomes. Immunoblotting experiments on dermal fibroblast culture medium showed only a slightly diminished amount of fibulin-4 compared to control, which the authors suggested was consistent with the longer survival of the patient. In addition, immunoblotting after TGFB (190180) stimulation of patient fibroblast cultures indicated a significantly increased phosphorylated SMAD2 (601366) signal compared to controls, suggesting that mutation in FBLN4 has an effect on the TGFB signaling pathway.
In a female infant with arterial tortuosity and aneurysm (ARCL1B; 614437), who suffered a large hemispheric stroke at 5 weeks of age and died at age 18 months from cardiorespiratory failure, Renard et al. (2010) identified compound heterozygosity for a 377A-T transversion in exon 5 of the EFEMP2 gene, resulting in a glu126-to-val (E126V) substitution at an evolutionarily conserved residue in the DINE consensus sequence of the second cbEGF-like domain, and a 1-bp deletion (577delC; 604633.0007) in exon 6, causing a frameshift predicted to result in a premature termination codon (Q193Sfs*12). The unaffected parents were each heterozygous for 1 of the mutations, neither of which was present in 200 control chromosomes. Clinical features in this patient included a prominent forehead, mild hypertelorism, downslanting palpebral fissures, depressed nasal bridge, low-set and distorted external ears, and long fingers. Echocardiogram showed severe dilation of the ascending aorta and severe tortuosity of the entire aorta with hypoplasia of the transverse aortic arch, proximal descending, thoracic, and abdominal aorta. MRI showed severe tortuosity of the carotid and cerebral arteries.
For discussion of the 1-bp deletion in the EFEMP2 gene (577delC) that was found in compound heterozygous state in a patient with arterial tortuosity and aneurysm (ARCL1B; 614437) by Renard et al. (2010), see 604633.0006.
In a 7-year-old boy with arterial tortuosity, aneurysm, and joint laxity (ARCL1B; 614437), originally reported by Baspinar et al. (2005), Renard et al. (2010) identified homozygosity for a 1189G-A transition in exon 11 of the EFEMP2 gene, resulting in an ala397-to-thr (A397T) substitution at a highly conserved residue in the C-terminal fibulin-like module. His unaffected parents were heterozygous for the mutation.
In 21 patients, 11 male and 10 female, with autosomal recessive cutis laxa type 1B (ARCL1B; 614437), Kappanayil et al. (2012) identified homozygosity for an A-to-C transversion at nucleotide 608 in exon 7 of the EFEMP2 gene that resulted in an aspartic acid-to-alanine substitution at codon 203 (D203A). All patients were Muslims from the Mappila community of the Malabar region of the Indian state of Kerala; 8 came from consanguineous families. All parents tested were normal and carried this mutation in heterozygosity. Homozygosity was lethal in 17 of the 21 patients, who died at a median age of 4 months. In another patient from the same community, Kappanayil et al. (2012) detected compound heterozygosity for this mutation and a de novo missense mutation (604633.0010).
In 1 patient with autosomal recessive cutis laxa type 1B (ARCL1B; 614437) from the Indian Mappila community, Kappanayil et al. (2012) detected compound heterozygosity for an asp203-to-ala mutation (D203A; 604633.0009) and a de novo C-to-T transition at nucleotide 679 resulting in an arginine-to-cysteine substitution at codon 227 (R227C). The mutation was found on the paternal allele; paternity was proven. Both the D203A and R227C mutations occurred in the same calcium-binding EGF domain of FBLN4. While this patient had vascular abnormalities similar to those seen in D203A homozygotes, the majority of whom died before the age of 4 months, she remained asymptomatic at the age of 7 years.
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