FBLN5

Summary

FBLN5 (fibulin 5, HGNC:3602) is a protein-coding gene on chromosome 14q32.12, encoding Fibulin-5 (Q9UBX5). Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN.

The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3).

Source: NCBI Gene 10516 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cutis laxa, autosomal recessive, type 1A (Definitive, GenCC) — +7 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 691 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 115
• MANE Select transcript: NM_006329

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3602
Approved symbol	FBLN5
Name	fibulin 5
Location	14q32.12
Locus type	gene with protein product
Status	Approved
Aliases	EVEC, UP50, DANCE, ARMD3
Ensembl gene	ENSG00000140092
Ensembl biotype	protein_coding
OMIM	604580
Entrez	10516

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000267620, ENST00000342058, ENST00000554121, ENST00000554468, ENST00000556154, ENST00000556961, ENST00000557088, ENST00000557462, ENST00000557570, ENST00000706675, ENST00000706676, ENST00000706677, ENST00000706678, ENST00000706679, ENST00000706680, ENST00000706681, ENST00000895482, ENST00000895483, ENST00000895484, ENST00000969124

RefSeq mRNA: 6 — MANE Select: NM_006329 NM_001384158, NM_001384159, NM_001384160, NM_001384161, NM_001384162, NM_006329

CCDS: CCDS91919, CCDS9898

Canonical transcript exons

ENST00000342058 — 11 exons

Exon	Start	End
ENSE00000941311	91894950	91895072
ENSE00000941312	91891221	91891337
ENSE00000941313	91887193	91887312
ENSE00000941314	91882954	91883076
ENSE00000941315	91881292	91881418
ENSE00000941316	91877487	91877682
ENSE00002435886	91869411	91870385
ENSE00002524575	91947213	91947694
ENSE00003508270	91942907	91942961
ENSE00003546390	91940565	91940616
ENSE00003574297	91936947	91937201

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.2999 / max 1686.7825, expressed in 1188 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144563	10.8841	619
144564	10.3278	628
144572	7.2230	1051
144565	3.3544	591
144569	1.3214	369
144562	1.0378	287
144570	1.0206	351
144575	0.9021	469
144571	0.7689	324
144568	0.6904	298

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
thoracic aorta	UBERON:0001515	99.61	gold quality
ascending aorta	UBERON:0001496	99.60	gold quality
descending thoracic aorta	UBERON:0002345	99.59	gold quality
right lung	UBERON:0002167	99.36	gold quality
right coronary artery	UBERON:0001625	99.34	gold quality
stromal cell of endometrium	CL:0002255	99.22	gold quality
left coronary artery	UBERON:0001626	99.00	gold quality
aorta	UBERON:0000947	98.98	gold quality
coronary artery	UBERON:0001621	98.93	gold quality
gall bladder	UBERON:0002110	98.80	gold quality
artery	UBERON:0001637	98.55	gold quality
popliteal artery	UBERON:0002250	98.52	gold quality
tibial artery	UBERON:0007610	98.52	gold quality
right atrium auricular region	UBERON:0006631	98.50	gold quality
body of uterus	UBERON:0009853	98.44	gold quality
cardiac atrium	UBERON:0002081	98.41	gold quality
metanephros cortex	UBERON:0010533	98.41	gold quality
omental fat pad	UBERON:0010414	98.40	gold quality
peritoneum	UBERON:0002358	98.39	gold quality
left uterine tube	UBERON:0001303	98.04	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.04	gold quality
upper lobe of left lung	UBERON:0008952	97.81	gold quality
nerve	UBERON:0001021	97.72	gold quality
tibial nerve	UBERON:0001323	97.72	gold quality
decidua	UBERON:0002450	97.66	gold quality
endocervix	UBERON:0000458	97.65	gold quality
mucosa of stomach	UBERON:0001199	97.65	gold quality
upper lobe of lung	UBERON:0008948	97.62	gold quality
blood vessel layer	UBERON:0004797	97.40	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.16	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	1659.13
E-CURD-7	yes	1380.59
E-ENAD-21	yes	1380.59
E-MTAB-8142	yes	89.66
E-HCAD-10	yes	54.34
E-GEOD-134144	yes	34.14
E-MTAB-6678	yes	27.64
E-CURD-46	yes	22.07
E-MTAB-10287	yes	21.58
E-HCAD-9	yes	5.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, SMAD2, SMAD3, TWIST2

Literature-anchored findings (GeneRIF, showing 40)

• Direct interaction of the extracellular matrix protein DANCE with apolipoprotein(a) mediated by the kringle IV-type 2 domain. (PMID:12111551)
• Genetic heterogeneity of cutis laxa exists due to a heterozygous tandem duplication in the FBLN5 gene. (PMID:12618961)
• Missense mutations in the fibulin 5 gene were found in 1.7 percent of patients with AMD. (PMID:15269314)
• EcSOD-fibulin-5 interaction is needed for ecSOD binding to vascular tissues, regulating their O2*- levels. This is a new mechanism for controlling vascular redox state in the extracellular space in cardiovascular diseases with high oxidative stress. (PMID:15528465)
• Decreased fibulin-5 may contribute to the pathogenesis of aortic dissection by impairing elastic fiber assembly. (PMID:16153447)
• The interaction of elastin and fibulin-5 alleles results in elastic fibers susceptible to inflammatory destruction. (PMID:16374472)
• These studies demonstrate that induction of fibulin 5 gene expression in lung fibroblasts is mediated via canonical TGF-beta/Smad signaling and requires the PI3-kinase/Akt pathway. (PMID:16837650)
• Endothelial cell (EC) attachment and adhesion to an artificial surface is improved after fibulin-5 (FBLN5) gene transfer. With improved adhesion, EC transduced to express FBLN5 exhibits reduced proliferative rates. (PMID:16904068)
• Fibulin-5 is necessary for elastic fiber formation by facilitating the deposition of elastin onto a microfibrillar scaffold via direct molecular interactions. (PMID:17035250)
• ternary complex formation between fibrillin-1, fibulins, and tropoelastin demonstrated that fibulin-2 and -5 but much less fibulin-4, are able to act as molecular adaptors between fibrillin-1 and tropoelastin (PMID:17255108)
• Fibulin-5 protein potently induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils. (PMID:17371835)
• This study identified the beta1 integrins on primary smooth muscle cells that fibulin-5 interacts with, and showed that failure of fibulin-5 to activate these receptors limits cell spreading, migration and proliferation. (PMID:17472576)
• These results suggest a novel regulatory mechanism of elastic fiber assembly in which LTBP-2 regulates targeting of DANCE on suitable microfibrils to form elastic fibers. (PMID:17581631)
• the p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model (PMID:18185537)
• degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis (PMID:18222970)
• fibulin-5 is a critical component in the control of elastic fibre assembly by dermal fibroblasts (PMID:18341572)
• Fibulin-5 expression is decreased in vaginal biopsies from women with prolapse. Changes in fibulin expression may play a role in the development of pelvic organ prolapse. (PMID:18989607)
• Data revealed that fibulin-5 is able to separately interact with tropoelastin or fibrillin-1 in the culture medium. Moreover, elastin, fibrillin-1, and fibulin-5 co-localize in the extracellular matrix. (PMID:19167375)
• homozygous recessive mutations in exon 12 of the elastin gene (p.P211S) in three patients from two related consanguineous Syrian families;a polymorphism in the fibulin 5 gene in one seems to modify the phenotype, producing more severe symptoms (PMID:19194475)
• Results show substantially decreased gene signals for production of small leucine-rich repeat proteoglycans and fibulin-5 in pelvic organ prolapse. (PMID:19251763)
• There was decreased expression of fibulin-5 and increased expression of lysyl oxidase-like 1 in uterosacral ligaments in patients with pelvic organ prolapse, which suggests the possibility of defects in elastin synthesis. (PMID:19450918)
• fibulin-5 controlled elastin deposition on microfibrils, although fibulin-4 can also bind fibrillin-1. (PMID:19570982)
• fibulin 5 functions as a dimer during elastinogenesis or that dimerization may provide a method for limiting interactions with binding partners such as tropoelastin. (PMID:19617354)
• Data show that the growth rate of the fibulin-5 transfected GFP-F5 cells was remarkably reduced than that of the untransfected cells. (PMID:19767220)
• FIB-5 expression is decreased in uterosacral ligaments of women with uterine prolapse. (PMID:19862539)
• The decreased expression of elastin and fibulin-5 was correlated with degree of pelvic organ prolapse. (PMID:19957551)
• The results identified structural differences for the disease-causing cutis laxa mutants and for one AMD (age-related macular degeneration) variant (G412E), suggesting that this may also be pathogenic. (PMID:20007835)
• genetic variation within FBLN5 is unlikely to play any role in the development of abdominal aortic aneurysm (PMID:20133342)
• Biophysical characterisation of fibulin-5 proteins associated with disease (PMID:20599547)
• Fibulin-5, a secreted extracellular matrix protein, was identified as a binding partner of Nogo-B. (PMID:20599731)
• The expression of EVEC in ovarian cancer and its metastatic sites was remarkably decreased. (PMID:21122382)
• HIF-1 signaling underlies the increase of FBLN5 expression elicited by hypoxia in endothelial cells suggesting that FBLN5 induction could be involved in the adaptive survival response of endothelial cells to hypoxia (PMID:21193390)
• spatiotemporal shift from the trophoblast compartment in first trimester to the villous vasculature at term suggests a dual role of fibulin-5 in human placental development. (PMID:21290250)
• Role of fibulin-5 in metastatic organ colonization (PMID:21454378)
• MMP9 and fibulin-5 have roles in progression of pelvic organ prolapse in mice and humans (PMID:21519142)
• This study identifies fibulin-5 as a gene involved in Charcot-Marie-Tooth neuropathies and reveals heterozygous fibulin-5 mutations in 2% of our patients with age-related macular degeneration and hyperelastic skin. (PMID:21576112)
• suggest that uPA promotes cell migration by binding to fibulin-5, initiating its cleavage by plasmin, which leads to its dissociation from beta1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility (PMID:22280367)
• Data suggest that expression of FBLN5 (fibulin 5) and LOXL1 (lysyl oxidase-like protein 1) (but not expression of elastin) is down-regulated in uterosacral ligaments of postmenopausal women with pelvic organ prolapse. (PMID:22487196)
• Altered expression of miR-200c may have a significant impact on the outcome of leiomyomas growth, maintenance of their mesenchymal and fibrotic characteristics, and possibly their associated symptoms. (PMID:22685266)
• fibulin-5 is reduced in patients with primary spontaneous pneumothorax who are younger than 25 years of age. (PMID:22790990)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbln5	ENSDARG00000039273
mus_musculus	Fbln5	ENSMUSG00000021186
rattus_norvegicus	Fbln5	ENSRNOG00000050539

Paralogs (6): FBLN1 (ENSG00000077942), EFEMP1 (ENSG00000115380), VWDE (ENSG00000146530), FBLN2 (ENSG00000163520), EFEMP2 (ENSG00000172638), EYS (ENSG00000188107)

Protein

Protein identifiers

Fibulin-5 — Q9UBX5 (reviewed: Q9UBX5)

Alternative names: Developmental arteries and neural crest EGF-like protein, Urine p50 protein

All UniProt accessions (10): Q9UBX5, A0A024R6G3, A0A9L9PX66, A0A9L9PXD9, A0A9L9PY85, G3V2P8, G3V329, G3V3Y2, G3V4U0, G3XA98

UniProt curated annotations — full annotation on UniProt →

Function. Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN. Stabilizes and organizes elastic fibers in the skin, lung and vasculature. Promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. Vascular ligand for integrin receptors which may play a role in vascular development and remodeling. May act as an adapter that mediates the interaction between FBN1 and ELN.

Subunit / interactions. Homodimer. Monomer, homodimerizes in presence of Ca(2+). Interacts with ELN. Interacts (via N-terminus) with the integrins ITGAV/ITGB3, ITGAV/ITGB5 and ITGA9/ITGB1. Interacts with FBN1 (via N-terminal domain). Forms a ternary complex with ELN and FBN1. Interacts with EFEMP2 with moderate affinity. Interacts with LOXL1.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in skin fibroblasts (at protein level). Expressed predominantly in heart, ovary, and colon but also in kidney, pancreas, testis, lung and placenta. Not detectable in brain, liver, thymus, prostate, or peripheral blood leukocytes.

Post-translational modifications. N-glycosylated.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 1H (CMT1H) [MIM:619764] An autosomal dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. CMT1H is characterized by peripheral sensorimotor neuropathy with onset usually in adulthood. Affected individuals present with foot deformities, upper or lower limb sensory disturbances, and motor deficits, mainly impaired gait. Rare patients may have hyperelastic skin or develop age-related macular degeneration. The disease is caused by variants affecting the gene represented in this entry. Cutis laxa, autosomal dominant, 2 (ADCL2) [MIM:614434] A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. Additional variable clinical features are gastrointestinal diverticula, hernia, and genital prolapse. Rare manifestations are pulmonary artery stenosis, aortic aneurysm, bronchiectasis, and emphysema. The disease is caused by variants affecting the gene represented in this entry. Cutis laxa, autosomal recessive, 1A (ARCL1A) [MIM:219100] A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. Type I autosomal recessive cutis laxa is a specific, life-threatening disorder with organ involvement, lung atelectasis and emphysema, diverticula of the gastrointestinal and genitourinary systems, and vascular anomalies. Associated cranial anomalies, late closure of the fontanel, joint laxity, hip dislocation, and inguinal hernia have been observed but are uncommon. The disease is caused by variants affecting the gene represented in this entry. Mutations affecting this gene can modify the phenotype of diseases caused by ELN mutations. Macular degeneration, age-related, 3 (ARMD3) [MIM:608895] A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the fibulin family.

RefSeq proteins (6): NP_001371087, NP_001371088, NP_001371089, NP_001371090, NP_001371091, NP_006320* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026823	cEGF	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR052235	Nephronectin_domain	Family
IPR055088	Fibulin_C	Domain

Pfam: PF07645, PF12662, PF22914

UniProt features (50 total): sequence variant 18, disulfide bond 17, domain 6, sequence conflict 3, glycosylation site 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBX5-F1	83.69	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (17): 46–59, 53–68, 131–144, 138–153, 155–166, 172–181, 177–190, 192–205, 211–221, 217–230, 232–245, 251–262, 258–271, 273–286, 292–305, 299–314, 320–332

Glycosylation sites (2): 283, 296

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1566948	Elastic fibre formation
R-HSA-2129379	Molecules associated with elastic fibres

MSigDB gene sets: 0 (showing top):

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), cell-matrix adhesion (GO:0007160), negative regulation of angiogenesis (GO:0016525), positive regulation of osteoblast proliferation (GO:0033690), protein localization to cell surface (GO:0034394), positive regulation of transcription by RNA polymerase II (GO:0045944), secretion (GO:0046903), elastic fiber assembly (GO:0048251), intramembranous bone growth (GO:0098867), regulation of removal of superoxide radicals (GO:2000121), cell adhesion (GO:0007155), extracellular matrix organization (GO:0030198)

GO Molecular Function (5): integrin binding (GO:0005178), calcium ion binding (GO:0005509), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), extracellular matrix constituent conferring elasticity (GO:0030023)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), elastic fiber (GO:0071953)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Extracellular matrix organization	1
Elastic fibre formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	1
cell-substrate adhesion	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
positive regulation of cell population proliferation	1
osteoblast proliferation	1
regulation of osteoblast proliferation	1
intracellular protein localization	1
positive regulation of DNA-templated transcription	1
transport	1
extracellular matrix assembly	1
supramolecular fiber organization	1
bone growth	1
removal of superoxide radicals	1
regulation of superoxide metabolic process	1
regulation of cellular response to oxidative stress	1
regulation of response to reactive oxygen species	1
cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
metal ion binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
extracellular matrix structural constituent	1
structural molecule activity conferring elasticity	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1
supramolecular fiber	1
non-collagenous component of interstitial matrix	1

Protein interactions and networks

STRING

2044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBLN5	ELN	P15502	997
FBLN5	LOXL1	Q08397	991
FBLN5	LOX	P28300	900
FBLN5	FBN1	P35555	884
FBLN5	ATP6V0A2	Q9Y487	863
FBLN5	FN1	P02751	859
FBLN5	LTBP2	Q14767	809
FBLN5	ADAMTS2	O95450	779
FBLN5	RIN2	Q8WYP3	778
FBLN5	LOXL2	Q9Y4K0	770
FBLN5	MFAP2	P55001	723
FBLN5	ADAMTS4	O75173	705
FBLN5	LTBP3	Q9NS15	697
FBLN5	PYCR1	P32322	693
FBLN5	COL3A1	P02461	655

IntAct

84 interactions, top by confidence:

A	B	Type	Score
NUFIP2	FBLN5	psi-mi:“MI:0915”(physical association)	0.800
FBLN5	NUFIP2	psi-mi:“MI:0915”(physical association)	0.800
rep	GTF2F2	psi-mi:“MI:0914”(association)	0.730
FBLN5	ELN	psi-mi:“MI:0407”(direct interaction)	0.610
ELN	FBLN5	psi-mi:“MI:0407”(direct interaction)	0.610
EFEMP2	FBLN5	psi-mi:“MI:0407”(direct interaction)	0.610
FBLN5	EFEMP2	psi-mi:“MI:0915”(physical association)	0.610
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
FBLN5	LOX	psi-mi:“MI:0915”(physical association)	0.570
FBLN5	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
FBLN5	OTX1	psi-mi:“MI:0915”(physical association)	0.560
FBLN5	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
FGFR3	FBLN5	psi-mi:“MI:0915”(physical association)	0.560
GRN	FBLN5	psi-mi:“MI:0915”(physical association)	0.560
WFS1	FBLN5	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	FBLN5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (173): FBLN5 (Reconstituted Complex), FBLN5 (Affinity Capture-Western), FBLN5 (Two-hybrid), MEOX2 (Two-hybrid), OTX1 (Two-hybrid), TRIP13 (Two-hybrid), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Affinity Capture-MS), FBLN5 (Reconstituted Complex), FBLN5 (Affinity Capture-Western)

ESM2 similar proteins: A2VCU8, A6QR11, O35568, O42182, O55058, O73775, O95967, P07224, P23142, P31515, P35555, P35556, P53813, P60755, P60756, P98118, P98133, Q01974, Q03610, Q08761, Q08879, Q0WYX8, Q12805, Q2VWQ2, Q5EA62, Q5R3Z7, Q5RA73, Q5RC26, Q61220, Q61554, Q61555, Q62918, Q62919, Q7YQD7, Q7Z553, Q7ZXL5, Q8BPB5, Q8MJJ9, Q8UVJ7, Q90827

Diamond homologs: A8WGB1, B3EWY9, B5DFC9, E1BMV3, G3V928, O19045, O43897, O57382, O73775, O75095, O88322, O88947, P00743, P07204, P07225, P10493, P13497, P14543, P15306, P21941, P23142, P25155, P25723, P35951, P37889, P48960, P51942, P53813, P98063, P98069, P98070, P98095, P98118, P98157, P98163, Q07954, Q08761, Q08879, Q09165, Q14112

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FBLN5	up-regulates	ELN	binding
FBLN5	“up-regulates activity”	ELN	binding
FBN1	“down-regulates activity”	FBLN5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Elastic fibre formation	5	49.4×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

691 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	332
Likely benign	264
Benign	43

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1342916	NM_006329.4(FBLN5):c.986A>T (p.Asp329Val)	Pathogenic
21452	NM_006329.3(FBLN5):c.380-9061_873dup	Pathogenic
2882131	NM_006329.4(FBLN5):c.479G>A (p.Trp160Ter)	Pathogenic
689758	NM_006329.4(FBLN5):c.1201_1202del (p.Ser401fs)	Pathogenic
995864	NM_006329.4(FBLN5):c.1134T>G (p.Tyr378Ter)	Pathogenic
1163081	NM_006329.4(FBLN5):c.850C>T (p.Arg284Ter)	Likely pathogenic
3065380	NM_006329.4(FBLN5):c.160C>T (p.Arg54Ter)	Likely pathogenic

SpliceAI

2433 predictions. Top by Δscore:

Variant	Effect	Δscore
14:91877683:C:CC	acceptor_gain	1.0000
14:91881288:TTACT:T	donor_loss	1.0000
14:91881289:TAC:T	donor_loss	1.0000
14:91881290:A:AC	donor_gain	1.0000
14:91881290:A:T	donor_loss	1.0000
14:91881291:C:CA	donor_loss	1.0000
14:91881291:C:CC	donor_gain	1.0000
14:91881291:CTTAT:C	donor_gain	1.0000
14:91881295:T:C	donor_gain	1.0000
14:91881416:TGT:T	acceptor_gain	1.0000
14:91881424:A:AC	acceptor_gain	1.0000
14:91881424:A:C	acceptor_gain	1.0000
14:91885975:T:TA	donor_gain	1.0000
14:91887213:T:TA	donor_gain	1.0000
14:91887226:AT:A	donor_gain	1.0000
14:91891335:TGT:T	acceptor_gain	1.0000
14:91891335:TGTC:T	acceptor_loss	1.0000
14:91891336:GTCTG:G	acceptor_loss	1.0000
14:91891337:TC:T	acceptor_loss	1.0000
14:91891338:C:CC	acceptor_gain	1.0000
14:91891338:C:T	acceptor_loss	1.0000
14:91891339:T:A	acceptor_loss	1.0000
14:91894945:GTTAC:G	donor_loss	1.0000
14:91894947:TA:T	donor_loss	1.0000
14:91894948:A:AT	donor_loss	1.0000
14:91894949:CC:C	donor_loss	1.0000
14:91894964:T:TA	donor_gain	1.0000
14:91895073:C:CC	acceptor_gain	1.0000
14:91937199:TAT:T	acceptor_gain	1.0000
14:91937200:ATCTG:A	acceptor_loss	1.0000

AlphaMissense

2958 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:91870255:A:G	L439P	1.000
14:91870318:A:G	L418P	1.000
14:91870360:A:G	L404P	1.000
14:91877497:A:C	F392C	1.000
14:91877530:A:C	F381C	1.000
14:91877530:A:G	F381S	1.000
14:91877575:A:C	F366C	1.000
14:91877650:C:G	C341S	1.000
14:91877651:A:G	C341R	1.000
14:91877651:A:T	C341S	1.000
14:91881340:C:G	C314S	1.000
14:91881341:A:T	C314S	1.000
14:91881406:C:G	C292S	1.000
14:91881407:A:T	C292S	1.000
14:91882959:C:G	C286S	1.000
14:91882960:A:G	C286R	1.000
14:91882960:A:T	C286S	1.000
14:91882999:A:G	C273R	1.000
14:91883003:G:C	C271W	1.000
14:91883004:C:T	C271Y	1.000
14:91883005:A:G	C271R	1.000
14:91883017:C:A	G267C	1.000
14:91883031:C:G	C262S	1.000
14:91883032:A:G	C262R	1.000
14:91883032:A:T	C262S	1.000
14:91883042:G:C	C258W	1.000
14:91883043:C:G	C258S	1.000
14:91883043:C:T	C258Y	1.000
14:91883044:A:G	C258R	1.000
14:91883044:A:T	C258S	1.000

dbSNP variants (sampled 300 via entrez): RS1000069928 (14:91883543 T>C), RS1000070793 (14:91946776 CAT>C), RS1000090638 (14:91937684 G>A), RS1000141687 (14:91906770 C>T), RS1000148752 (14:91929053 A>G), RS1000179117 (14:91874790 C>A), RS1000186326 (14:91897460 T>C), RS1000250035 (14:91918542 C>T), RS1000250931 (14:91900698 G>C), RS1000264725 (14:91886563 G>T), RS1000270576 (14:91881089 T>C), RS1000281862 (14:91880694 C>T), RS1000310288 (14:91920700 G>C), RS1000406509 (14:91894435 A>C), RS1000438399 (14:91926416 A>C,G)

Disease associations

OMIM: gene MIM:604580 | disease phenotypes: MIM:603075, MIM:614434, MIM:219100, MIM:608895, MIM:619764

GenCC curated gene-disease

Disease	Classification	Inheritance
cutis laxa, autosomal recessive, type 1A	Definitive	Autosomal recessive
cutis laxa, autosomal dominant 2	Definitive	Autosomal dominant
Charcot-Marie-Tooth disease, demyelinating, IIA 1H	Strong	Autosomal dominant
demyelinating hereditary motor and sensory neuropathy	Strong	Autosomal dominant
macular degeneration, age-related, 3	Moderate	Autosomal dominant
hereditary sensorimotor neuropathy with hyperelastic skin	Supportive	Autosomal dominant
autosomal dominant cutis laxa	Supportive	Autosomal dominant
autosomal recessive cutis laxa type 1	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
demyelinating hereditary motor and sensory neuropathy	Moderate	AD

Mondo (15): age-related macular degeneration (MONDO:0005150), cutis laxa, autosomal dominant 2 (MONDO:0013751), autosomal dominant cutis laxa (MONDO:0019571), inherited retinal dystrophy (MONDO:0019118), cutis laxa, autosomal recessive, type 1A (MONDO:0009052), macular degeneration, age-related, 3 (MONDO:0012145), Charcot-Marie-Tooth disease, demyelinating, IIA 1H (MONDO:0030689), cutis laxa (MONDO:0016175), hereditary sensorimotor neuropathy with hyperelastic skin (MONDO:0017237), optic atrophy (MONDO:0003608), age related macular degeneration 1 (MONDO:0011285), autosomal recessive cutis laxa type 1 (MONDO:0019572), proximal spinal muscular atrophy (MONDO:0019079), axonal neuropathy (MONDO:0004183), demyelinating hereditary motor and sensory neuropathy (MONDO:0018776)

Orphanet (7): Autosomal dominant cutis laxa (Orphanet:90348), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Hereditary sensorimotor neuropathy with hyperelastic skin (Orphanet:280598), Autosomal recessive cutis laxa type 1 (Orphanet:90349), Cutis laxa (Orphanet:209), Proximal spinal muscular atrophy (Orphanet:70), NON RARE IN EUROPE: Age-related macular degeneration (Orphanet:279)

HPO phenotypes

115 total (30 of 115 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000271	Abnormality of the face
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000519	Developmental cataract
HP:0000608	Macular degeneration
HP:0000729	Autistic behavior
HP:0000762	Decreased nerve conduction velocity
HP:0000767	Pectus excavatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000929	Abnormal skull morphology
HP:0000938	Osteopenia
HP:0000973	Cutis laxa
HP:0000974	Hyperextensible skin
HP:0001058	Poor wound healing
HP:0001166	Arachnodactyly
HP:0001181	Adducted thumb
HP:0001252	Hypotonia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000175_32	Height	1.000000e-10
GCST002702_77	Height	2.000000e-17
GCST006979_1013	Heel bone mineral density	4.000000e-09
GCST007096_100	Pulse pressure	4.000000e-14
GCST007097_135	Pulse pressure	1.000000e-07
GCST007097_136	Pulse pressure	4.000000e-09
GCST007268_49	Diastolic blood pressure	3.000000e-15
GCST007269_328	Pulse pressure	1.000000e-12
GCST008161_86	Waist circumference adjusted for body mass index	2.000000e-06
GCST008839_295	Height	3.000000e-07
GCST009462_81	Optic disc size	3.000000e-08
GCST009616_4	HDL cholesterol levels x thiazide or thiazide-like diuretics use interaction	3.000000e-07
GCST010396_196	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06
GCST012304_1	Major depressive disorder	6.000000e-06
GCST012305_3	Major depressive disorder x sex interaction	2.000000e-06
GCST90020028_1872	Hip circumference adjusted for BMI	1.000000e-12

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0007789	BMI-adjusted waist circumference
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement
EFO:0008343	sex interaction measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C562627	Cutis Laxa, Autosomal Dominant (supp.)
C562628	Cutis Laxa, Autosomal Recessive, Type I (supp.)
C536225	Cutis laxa, recessive (supp.)
C566411	Macular Degeneration, Age-Related, 1 (supp.)
C563838	Macular Degeneration, Age-Related, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	increases expression, increases methylation	2
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
pentanal	increases expression	1
octa-2,4,6-trienoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
3-nitrobenzanthrone	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LG 100815	increases expression	1
Bortezomib	decreases expression	1
Dasatinib	increases expression	1
Resveratrol	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Aldehydes	increases expression	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00134667	PHASE4	TERMINATED	Macugen (Pegaptanib Sodium) Alone, Versus Macugen in Combination With PDT (Photodynamic Therapy) With Visudyne (Verteporfin) in Patients With Age-Related Macular Degeneration (AMD)
NCT00135837	PHASE4	COMPLETED	Photodynamic Therapy in Occult-Only Lesions (POOL)
NCT00327470	PHASE4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00331435	PHASE4	COMPLETED	PDT Study for Exudative AMD With PCV
NCT00354445	PHASE4	UNKNOWN	A Clinical Trial to Explore the Safety and Efficacy of Injections of Macugen When Given Every 6 Weeks in Subjects With AMD
NCT00423189	PHASE4	TERMINATED	Lucentis Utilizing Visudyne (LUV Trial) Combination Therapy in the Treatment of Age-Related Macular Degeneration
NCT00478439	PHASE4	TERMINATED	Investigation of Macular Pigment Augmentation on Dark Adaptation
NCT00556348	PHASE4	COMPLETED	Intravitreal Bevacizumab for Choridal Neovascularization Secondary to Age-Related Macular Degeneration
NCT00680498	PHASE4	COMPLETED	Combination Lucentis and Ocular Photodynamic Therapy With Visudyne, With Evaluation-based Retreatment
NCT00805649	PHASE4	COMPLETED	Combined Therapy in Age-Related Macular Degeneration (ARMD)
NCT01148511	PHASE4	COMPLETED	Comparison of Safety, Effectiveness and Quality of Life Outcomes Between Labeled Versus Treat and Extend Regimen in Turkish Patients With Choroidal Neovascularisation Due to Age-related Macular Degeneration (AMD)
NCT01165801	PHASE4	COMPLETED	Size Progression of Macular Degeneration After Cataract Surgery
NCT01319188	PHASE4	TERMINATED	Ranibizumab and the Risk of Arterial Thromboembolic Events
NCT01453920	PHASE4	COMPLETED	Wet AMD Recurrence Rate in Patients Stable on Three Month Ranibizumab Dosing
NCT01464723	PHASE4	COMPLETED	Study EvAluating Genotypes While Using Lucentis 2
NCT01495221	PHASE4	COMPLETED	To Evaluate The Role of Intravitreal Aflibercept Injection (2.0 mg) in the Management of Previously Treated Patients With Exudative AMD
NCT01543568	PHASE4	COMPLETED	Study for Recalcitrant Age Related Macular Degeneration
NCT01573572	PHASE4	COMPLETED	Extension Study to Gather Data on Effect of Macugen on the Corneal Endothelium
NCT01657669	PHASE4	UNKNOWN	Short-term Clinical Effects of Intravitreal Aflibercept Injection 2.0mg as a Predictor of Long-term Results
NCT01670162	PHASE4	UNKNOWN	On-label tReatment With Intravitreal Aflibercept injectiOn for Patients With Persistent Pigment epitheliaL Detachments in Neovascular Age Related Macular Degeneration (AMD)
NCT01824225	PHASE4	COMPLETED	Study of PRN and Every 2months Intravitreal Aflibercept for Age Related Macular Degeneration
NCT01846273	PHASE4	COMPLETED	Visual Outcome in Patients With Symptomatic Macular Polypoidal Choroidal Vasculopathy (PCV) Treated With Either Ranibizumab as Monotherapy or Combined With Verteporfin Photodynamic Therapy (vPDT)
NCT01943396	PHASE4	UNKNOWN	Treatment of AMD With Rheohemapheresis /RHF/
NCT02002377	PHASE4	TERMINATED	Intravitreal Aflibercept in Wet Age Related Macular Degeneration Patients With an Incomplete Response to Routine Ranibizumab Injections
NCT02130024	PHASE4	COMPLETED	A Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients
NCT02140411	PHASE4	COMPLETED	Efficacy and Safety of Lucentis® (Ranibizumab Intravitreal Injections) in Chilean Patients With Diabetic Macular Edema.
NCT02441816	PHASE4	COMPLETED	VITAL - Individualising Therapy for Neovascular AMD With Aflibercept
NCT02577107	PHASE4	COMPLETED	Head to Head Study of Anti-VEGF Treatment.
NCT02681783	PHASE4	UNKNOWN	PRedictive Factors and Changes From Treatment in iPCV Versus CSR Versus nAMD With afLibercept
NCT02802657	PHASE4	UNKNOWN	Efficacy and Safety of Treat-and-Extend Regimen Versus Pro Re Nata of Conbercept in Age-related Macular Degeneration
NCT02864472	PHASE4	UNKNOWN	Comparison of PDT Combination With Ranibizumab vs. Ranibizumab Monotherapy in Persistent PCV With Initial Loading Dose
NCT03056079	PHASE4	UNKNOWN	Cytokine and Visual Outcome Variations in Eyes Receiving Aflibercept
NCT03056092	PHASE4	UNKNOWN	Cytokine and Visual Outcome Variations in Eyes Receiving Ranibizumab
NCT03117634	PHASE4	COMPLETED	An Open Label-study to Compare the Efficacy of Aflibercept Monotherapy for Polypoidal Choroidal Vasculopathy
NCT03205202	PHASE4	UNKNOWN	Cataract and AMD in a Trial of a Multivitamin and Cocoa Extract
NCT03393767	PHASE4	COMPLETED	Time Course of Activity Signs at SD-OCT High Frequency Intravitreal Ranibizumab Treatment in CNV Due to AMD
NCT03409250	PHASE4	COMPLETED	SD-OCT-guided Intravitreal Ranibizumab Treatment in Choroidal Neovascularization Due to Myopia
NCT03552770	PHASE4	COMPLETED	Single or Combined Protocols for NV-AMD
NCT04018482	PHASE4	COMPLETED	Povidone Iodine vs AVEnova: A Pre-injection Disinfection Study (PAVE Study)
NCT04679935	PHASE4	COMPLETED	Efficacy and Safety of Two Different Brolucizumab 6 mg Dosing Regimens in Neovascular Age-related Macular Degeneration