FBN1

Summary

FBN1 (fibrillin 1, HGNC:3603) is a protein-coding gene on chromosome 15q21.1, encoding Fibrillin-1 (P35555). Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome.

Source: NCBI Gene 2200 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Marfan syndrome (Definitive, ClinGen) — +11 more curated relationships
• GWAS associations: 30
• Clinical variants (ClinVar): 9,261 total — 2056 pathogenic, 1124 likely-pathogenic
• Phenotypes (HPO): 312
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3603
Approved symbol	FBN1
Name	fibrillin 1
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	MASS, OCTD, SGS
Ensembl gene	ENSG00000166147
Ensembl biotype	protein_coding
OMIM	134797
Entrez	2200

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 retained_intron, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000316623, ENST00000537463, ENST00000558230, ENST00000559133, ENST00000560355, ENST00000560820, ENST00000561429, ENST00000674301, ENST00000682158, ENST00000682170, ENST00000682767, ENST00000683268, ENST00000684448, ENST00000714128

RefSeq mRNA: 3 — MANE Select: NM_000138 NM_000138, NM_001406716, NM_001406718

CCDS: CCDS32232

Canonical transcript exons

ENST00000316623 — 66 exons

Exon	Start	End
ENSE00000884488	48428346	48428471
ENSE00001599991	48515387	48515527
ENSE00001612341	48497266	48497391
ENSE00001613423	48488368	48488493
ENSE00001613453	48483818	48483943
ENSE00001620699	48485374	48485496
ENSE00001630897	48496100	48496225
ENSE00001640683	48498985	48499038
ENSE00001641154	48487312	48487437
ENSE00001661869	48495123	48495260
ENSE00001666782	48508582	48508704
ENSE00001675795	48510044	48510169
ENSE00001699841	48516183	48516362
ENSE00001715942	48503787	48503939
ENSE00001717687	48489851	48490078
ENSE00001721875	48505025	48505147
ENSE00001729100	48610728	48610826
ENSE00001737946	48600139	48600234
ENSE00001744589	48520659	48520817
ENSE00001753582	48481655	48481780
ENSE00001761744	48613010	48613092
ENSE00001762721	48488113	48488241
ENSE00001764592	48537611	48537808
ENSE00001769793	48492461	48492586
ENSE00001771562	48526130	48526255
ENSE00001772761	48495469	48495588
ENSE00001783191	48596283	48596378
ENSE00001788059	48513549	48513668
ENSE00001788284	48494204	48494254
ENSE00001793339	48534080	48534205
ENSE00001800492	48487075	48487200
ENSE00002265829	48408313	48411379
ENSE00002704173	48644606	48644950
ENSE00003458562	48445376	48445504
ENSE00003487267	48474255	48474377
ENSE00003504097	48420687	48420806
ENSE00003512063	48421952	48422068
ENSE00003515783	48430671	48430802
ENSE00003523525	48452562	48452684
ENSE00003531791	48432866	48432988
ENSE00003549123	48468412	48468534
ENSE00003571879	48415536	48415767
ENSE00003572869	48425739	48425864
ENSE00003573277	48446706	48446822
ENSE00003574914	48472551	48472676
ENSE00003575380	48434594	48434713
ENSE00003576310	48441721	48441846
ENSE00003578552	48456637	48456762
ENSE00003582511	48470634	48470756
ENSE00003583402	48437768	48437917
ENSE00003586121	48474528	48474650
ENSE00003586613	48437322	48437387
ENSE00003597898	48436961	48437077
ENSE00003600692	48465568	48465693
ENSE00003603774	48427567	48427773
ENSE00003605533	48460246	48460317
ENSE00003611210	48421558	48421686
ENSE00003620113	48465790	48465858
ENSE00003637858	48463899	48464021
ENSE00003645728	48463082	48463240
ENSE00003655251	48444541	48444660
ENSE00003663243	48425369	48425491
ENSE00003666049	48412569	48412743
ENSE00003679783	48467938	48468102
ENSE00003691172	48448768	48448893
ENSE00003899411	48645575	48645709

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.0030 / max 2239.4046, expressed in 1300 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149782	70.5909	1282
149781	7.4809	860
149780	0.6345	318
149783	0.3899	206
149779	0.2515	127
149784	0.2279	123
149777	0.2134	105
149785	0.1411	49
149778	0.0535	20
149766	0.0195	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.71	gold quality
skin of hip	UBERON:0001554	99.68	gold quality
decidua	UBERON:0002450	99.43	gold quality
stromal cell of endometrium	CL:0002255	99.20	gold quality
mammalian vulva	UBERON:0000997	99.17	gold quality
pericardium	UBERON:0002407	99.11	gold quality
periodontal ligament	UBERON:0008266	99.04	gold quality
vena cava	UBERON:0004087	99.00	gold quality
parietal pleura	UBERON:0002400	98.83	gold quality
placenta	UBERON:0001987	98.60	gold quality
saphenous vein	UBERON:0007318	98.55	gold quality
pleura	UBERON:0000977	98.51	gold quality
urethra	UBERON:0000057	98.46	gold quality
visceral pleura	UBERON:0002401	98.34	gold quality
tibia	UBERON:0000979	98.05	gold quality
right coronary artery	UBERON:0001625	97.95	gold quality
upper leg skin	UBERON:0004262	97.81	gold quality
penis	UBERON:0000989	97.47	gold quality
coronary artery	UBERON:0001621	97.28	gold quality
left coronary artery	UBERON:0001626	97.27	gold quality
descending thoracic aorta	UBERON:0002345	97.27	gold quality
cauda epididymis	UBERON:0004360	97.27	gold quality
superficial temporal artery	UBERON:0001614	97.24	gold quality
mucosa of stomach	UBERON:0001199	97.23	gold quality
mammary duct	UBERON:0001765	97.12	gold quality
thoracic aorta	UBERON:0001515	97.03	gold quality
heart right ventricle	UBERON:0002080	97.03	gold quality
ascending aorta	UBERON:0001496	96.99	gold quality
diaphragm	UBERON:0001103	96.95	gold quality
pharyngeal mucosa	UBERON:0000355	96.92	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	2725.16
E-MTAB-8322	yes	1786.41
E-MTAB-10662	yes	324.99
E-MTAB-10287	yes	102.86
E-MTAB-8142	yes	89.57
E-HCAD-1	yes	74.79
E-MTAB-8410	yes	55.26
E-HCAD-10	yes	41.09
E-GEOD-134144	yes	34.27
E-MTAB-9543	yes	20.30
E-CURD-119	yes	11.27
E-GEOD-83139	yes	7.30
E-CURD-112	yes	6.13
E-GEOD-130148	yes	5.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MMP1	Activation

Upstream regulators (CollecTRI, top): BARX1, DCN, EMX2, FOXO1, HAND2, HOXD13, IGF1, IGF1R, IL1A, PARP1, SP1, TAL1, TLX3

miRNA regulators (miRDB)

160 targeting FBN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-512-3P	99.97	67.35	1049

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Characterised five novel missense mutations (C474W, C1402Y, G1987R, C2153Y, G2536R), one novel frameshift mutation (7926delC). (PMID:11524736)
• FBN1 screening could be a helpful tool to confirm and possibly anticipate the clinical diagnosis in familial cases. (PMID:11748851)
• NMR study of effects of N2144S mutation on backbone dynamics of a TB-cbEGF domain pair from human fibrillin-1 (PMID:11829507)
• Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene (PMID:11933199)
• a nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer (PMID:12130535)
• Sequence analysis revealed eight coding and 14 non-coding SNPs and other polymorphisms. Among them, a CT insertion in the 5’-untranslated region of exon A had a significant negative association with disease. (PMID:12384286)
• interactions with fibrillin-2 constitute the basis for the assembly of microfibrils (PMID:12399449)
• fibrillin-1 is found associated with latent transforming growth factor beta-binding protein 1 in microfibrils (PMID:12429738)
• there is a molecular basis for compensation of one fibrillin (1 or 2) by the other during fetal life (PMID:12429739)
• all fibrillin-1 (cb)EGF-cbEGF pairs, characterized by a single interdomain linker residue, possess this rod-like structure. The domain arrangement of cbEGF12-13 is stabilized by additional interdomain packing interactions (PMID:12511552)
• In kidney, liver, rib anlagen, notochord fibrillin-1 and fibrillin-2 are distributed differentially. Different roles for fibrillin-1 and -2 in the development of these structures. (PMID:12524050)
• An in frame fibrillin-1 gene deletion shows that autosomal dominant Weill-Marchesani syndrome and Marfan syndrome are allelic conditions at the fibrillin-1 locus. (PMID:12525539)
• A missense mutation is described for this gene. (PMID:12575662)
• relaxin does not regulate its mRNA and protein expression by human dermal fibroblasts and murine fetal skin. (PMID:12590922)
• disease associated with missense mutations in FBN1 is caused either by an intracellular dominant negative effect or haploinsufficiency (PMID:12651868)
• fibrillin-1 has a role in mediating cell adhesion (PMID:12807887)
• Allelic variation in normal FBN1 expression was found in a family with Marfan syndrome. (PMID:12915484)
• Patients with mitral valve prolapse (MVP) have higher frequencies of fibrillin-1 (FBN1) exon 15 TT and exon 27 GG genotypes, which supports a role of the FBN1 exon 15 and 27 polymorphisms in determining the risk of MVP. (PMID:12918850)
• Results describe the intrinsic elastic properties of individual fibrillin microfibrils, which act as reinforcing fibres in fibrous composite tissues. (PMID:12946356)
• In a patient with neonatal Marfan syndrome, molecular analysis showed a heterozygous missense mutation at nucleotide 3165 (3165T>G) in exon 25 of the FBN1 gene, resulting in the substitution of cysteine for tryptophan (C1055W). (PMID:14586646)
• FBN1 is the most likely candidate gene on the chromosome 15 haplotype associated with systemic sclerosis in the Choctaw Indians. (PMID:14613297)
• defect in fibrillin-1 containing microfibrils in dermal fibroblasts from systemic sclerosis patients (PMID:14730633)
• We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before. (PMID:15054843)
• Results identify MAGP-2 binding regions in the N-terminal portion of fibrillin-1 and -2 molecules. (PMID:15131124)
• Mutations in FBN1 gene are not responsible for the manifestation of the autosomal dominant form of familial spontaneous penumothorax. (PMID:15161620)
• cysteine mutations have an effect in calcium-binding epidermal growth factor modules of fibrillin-1 (PMID:15161917)
• eightfive novel mutations were identified in FBN1 in 93 classical Marfan syndrome patients. (PMID:15241795)
• Data are consistent with a model that invokes haploinsufficiency for wild type fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly in Marfan syndrome. (PMID:15254584)
• cysteine in calcium-binding epidermal growth factor-like domain 30 of human fibrillin-1 have roles in stability and cellular trafficking of proteins (PMID:15371449)
• fibrillin-1 interactions regulate microfibril assembly (PMID:15569675)
• Results describe the binding characteristics of six fibrillin-1 calcium-binding epidermal growth factor-like domains, each preceded by a transforming growth factor beta-binding protein-like (TB) domain. (PMID:15649891)
• abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin. (PMID:15654955)
• High affinity interactions between fibrillin-1 and perlecan were found by kinetic binding studies with dissociation constants in the low nanomolar range. (PMID:15657057)
• The phenotypic similarities between homocystinuria and Marfan syndrome suggest that elevated homocysteine levels may result in an altered function of fibrillin-1. (PMID:15713466)
• Marfan syndrome, the founding member of connective tissue disorders, is characterized by involvement of three major systems (skeletal, ocular, and cardiovascular) due to alteration in microfibrils. FBN1 at 15q21. (PMID:15861007)
• analysis of heparin binding to fibrillin-1 (PMID:15980072)
• Domain 16 of fibrillin-1 is an anchor point for tropoelastin at the microfibril-elastin junction during the initial stages of elastic fiber assembly. (PMID:16042404)
• structural and functional modifications as well as degradation processes of fibrillin-1 in the connective tissues of patients with homocystinuria play a major role in the pathogenesis of this disorder (PMID:16096271)
• In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease. (PMID:16103519)
• Sixty-two novel mutations within the FBN1 gene are associated with Marfan syndrome and other fibrillinopathies. (PMID:16222657)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fbn1	ENSMUSG00000027204
rattus_norvegicus	Fbn1	ENSRNOG00000007302

Paralogs (2): FBN2 (ENSG00000138829), FBN3 (ENSG00000142449)

Protein

Protein identifiers

Fibrillin-1 — P35555 (reviewed: P35555)

All UniProt accessions (5): A0A6I8PL22, P35555, F6U495, H0YN80, H0YND0

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues. Fibrillin-1-containing microfibrils provide long-term force bearing structural support. In tissues such as the lung, blood vessels and skin, microfibrils form the periphery of the elastic fiber, acting as a scaffold for the deposition of elastin. In addition, microfibrils can occur as elastin-independent networks in tissues such as the ciliary zonule, tendon, cornea and glomerulus where they provide tensile strength and have anchoring roles. Fibrillin-1 also plays a key role in tissue homeostasis through specific interactions with growth factors, such as the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and latent transforming growth factor-beta-binding proteins (LTBPs), cell-surface integrins and other extracellular matrix protein and proteoglycan components. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively. Negatively regulates osteoclastogenesis by binding and sequestering an osteoclast differentiation and activation factor TNFSF11. This leads to disruption of TNFSF11-induced Ca(2+) signaling and impairment of TNFSF11-mediated nuclear translocation and activation of transcription factor NFATC1 which regulates genes important for osteoclast differentiation and function. Mediates cell adhesion via its binding to cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1. Binds heparin and this interaction has an important role in the assembly of microfibrils. Adipokine secreted by white adipose tissue that plays an important regulatory role in the glucose metabolism of liver, muscle and pancreas. Hormone that targets the liver in response to fasting to increase plasma glucose levels. Binds the olfactory receptor OR4M1 at the surface of hepatocytes and promotes hepatocyte glucose release by activating the protein kinase A activity in the liver, resulting in rapid glucose release into the circulation. May act as a regulator of adaptive thermogenesis by inhibiting browning and energy consumption, while increasing lipid deposition in white adipose tissue. Also acts as an orexigenic hormone that increases appetite: crosses the blood brain barrier and exerts effects on the hypothalamus. In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation. Activates orexigenic AgRP neurons via binding to the olfactory receptor OR4M1. May also play a role in sperm motility in testis via interaction with OR4M1 receptor.

Subunit / interactions. Interacts with COL16A1. Interacts with integrin alpha-V/beta-3. Interacts with ADAMTS10; this interaction promotes microfibril assembly. Interacts with THSD4; this interaction promotes fibril formation. Interacts (via N-terminal domain) with FBLN2 and FBLN5. Interacts with ELN. Forms a ternary complex with ELN and FBLN2 or FBLN5 and a significant interaction with ELN seen only in the presence of FBLN2 or FBLN5. Interacts (via N-terminal domain) with LTBP2 (via C-terminal domain) in a Ca(+2)-dependent manner. Interacts (via N-terminal domain) with LTBP1 (via C-terminal domain). Interacts with integrins ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB6. Interacts (via N-terminal domain) with BMP2, BMP4, BMP7, BMP10 and GDF5. Interacts (via N-terminal domain) with MFAP2 and MFAP5. Interacts with ADAMTSL5. Interacts with MFAP4. Interacts (via N-terminal domain) with TNFSF11 in a Ca(+2)-dependent manner. Interacts (via N-terminal domain) with EFEMP2; this interaction inhibits EFEMP2 binding to LOX and ELN.

Subcellular location. Secreted Secreted. Extracellular space. Extracellular matrix Secreted.

Post-translational modifications. Cleavage of N- and C-terminus by furin is required for incorporation into the extracellular matrix and assembly into microfibrils. The C-terminus, which corresponds to the Asprosin chain, was initially thought to constitute a propeptide. Fibrillin-1 and Asprosin chains are still linked together during the secretion from cells, but are subsequently separated by furin, an essential step for incorporation of Fibrillin-1 into the nascent microfibrils. Forms intermolecular disulfide bonds either with other fibrillin-1 molecules or with other components of the microfibrils. O-glycosylated on serine residues by POGLUT2 and POGLUT3 which is necessary for efficient protein secretion.

Disease relevance. Marfan syndrome (MFS) [MIM:154700] A hereditary disorder of connective tissue that affects the skeletal, ocular, and cardiovascular systems. A wide variety of skeletal abnormalities occurs with Marfan syndrome, including scoliosis, chest wall deformity, tall stature, abnormal joint mobility. Ectopia lentis occurs in most of the patients and is almost always bilateral. The leading cause of premature death is progressive dilation of the aortic root and ascending aorta, causing aortic incompetence and dissection. Neonatal Marfan syndrome is the most severe form resulting in death from cardiorespiratory failure in the first few years of life. The disease is caused by variants affecting the gene represented in this entry. The majority of the more than a thousand mutations in FBN1 currently known are point mutations, the rest are frameshifts and splice site mutations. Marfan syndrome has been suggested in at least 2 historical figures, Abraham Lincoln and Paganini. Ectopia lentis 1, isolated, autosomal dominant (ECTOL1) [MIM:129600] An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation. The disease is caused by variants affecting the gene represented in this entry. Weill-Marchesani syndrome 2 (WMS2) [MIM:608328] A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma. The disease is caused by variants affecting the gene represented in this entry. Overlap connective tissue disease (OCTD) [MIM:604308] Heritable disorder of connective tissue characterized by involvement of the mitral valve, aorta, skeleton, and skin. MASS syndrome is closely resembling both the Marfan syndrome and the Barlow syndrome. However, no dislocation of the lenses or aneurysmal changes occur in the aorta, and the mitral valve prolapse is by no means invariable. The disease is caused by variants affecting the gene represented in this entry. Stiff skin syndrome (SSKS) [MIM:184900] A syndrome characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness. The disease is caused by variants affecting the gene represented in this entry. Geleophysic dysplasia 2 (GPHYSD2) [MIM:614185] An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a ‘happy’ face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues. The disease is caused by variants affecting the gene represented in this entry. Acromicric dysplasia (ACMICD) [MIM:102370] An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal. The disease is caused by variants affecting the gene represented in this entry. Marfanoid-progeroid-lipodystrophy syndrome (MFLS) [MIM:616914] An autosomal dominant syndrome characterized by congenital lipodystrophy, a progeroid facial appearance due to lack of subcutaneous fat, and variable signs of Marfan syndrome. Clinical features include premature birth with an accelerated linear growth disproportionate to the weight gain, ectopia lentis, aortic dilatation, dural ectasia, and arachnodactyly. Mental and motor development are within normal limits. The disease is caused by variants affecting the gene represented in this entry.

Induction. Asprosin levels are elevated in patients with type II diabetes and metabolic syndrome (at protein level).

Miscellaneous. Was named after the Greek word for white, because of the reduction in subcutaneous white adipose tissue that is displayed by asprosin-deficient patients.

Similarity. Belongs to the fibrillin family.

RefSeq proteins (3): NP_000129, NP_001393645, NP_001393647 (=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
IPR013032	EGF-like_CS	Conserved_site
IPR017878	TB_dom	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024731	NELL2-like_EGF	Domain
IPR026823	cEGF	Domain
IPR036773	TB_dom_sf	Homologous_superfamily
IPR040872	Fibrillin_U_N	Domain
IPR049388	FBN_EGF_N	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR052080	vWF_C/EGF_Fibrillin	Family

Pfam: PF00683, PF07645, PF12661, PF12662, PF12947, PF14670, PF18193, PF21364

UniProt features (836 total): sequence variant 464, disulfide bond 155, strand 63, domain 56, glycosylation site 42, turn 18, helix 15, region of interest 7, mutagenesis site 4, chain 2, site 2, modified residue 2, sequence conflict 2, signal peptide 1, propeptide 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1UZK	X-RAY DIFFRACTION	1.35
1UZP	X-RAY DIFFRACTION	1.78
2W86	X-RAY DIFFRACTION	1.8
1UZJ	X-RAY DIFFRACTION	2.25
1UZQ	X-RAY DIFFRACTION	2.4
1APJ	SOLUTION NMR
1EMN	SOLUTION NMR
1EMO	SOLUTION NMR
1LMJ	SOLUTION NMR
2M74	SOLUTION NMR
5MS9	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P35555 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (2): 44–45 (cleavage; by furin); 2731–2732 (cleavage; by furin)

Post-translational modifications (2): 2702, 2709

Disulfide bonds (155): 59–68, 67–80, 85–94, 89–100, 102–111, 119–129, 123–134, 136–145, 150–160, 154–166, 168–177, 250–262, 257–271, 273–286, 292–304, 299–313, 315–328, 453–465, 460–474, 476–488 …

Glycosylation sites (42): 1902, 1911, 1953, 2035, 2077, 2148, 2178, 2227, 2313, 2465, 2547, 2628, 2734, 2750, 2767, 268, 448, 471, 510, 552 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
1542	loss of integrin-mediated cell adhesion.
2728	abolishes furin cleavage site, leading to defects in protein processing at the c-terminus.
2731	abolishes furin cleavage site, leading to defects in protein processing at the c-terminus.
2732	defects in protein processing at the c-terminus.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1566948	Elastic fibre formation
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-216083	Integrin cell surface interactions
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 956 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, TGGTGCT_MIR29A_MIR29B_MIR29C, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_METANEPHROS_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT

GO Biological Process (20): skeletal system development (GO:0001501), metanephros development (GO:0001656), glucose metabolic process (GO:0006006), heart development (GO:0007507), gene expression (GO:0010467), cell adhesion mediated by integrin (GO:0033627), obsolete sequestering of BMP in extracellular matrix (GO:0035582), obsolete sequestering of TGFbeta in extracellular matrix (GO:0035583), glucose homeostasis (GO:0042593), camera-type eye development (GO:0043010), negative regulation of osteoclast differentiation (GO:0045671), embryonic eye morphogenesis (GO:0048048), post-embryonic eye morphogenesis (GO:0048050), lung alveolus development (GO:0048286), cellular response to transforming growth factor beta stimulus (GO:0071560), cellular response to insulin-like growth factor stimulus (GO:1990314), negative regulation of osteoclast development (GO:2001205), kidney development (GO:0001822), signal transduction (GO:0007165), lung development (GO:0030324)

GO Molecular Function (9): integrin binding (GO:0005178), hormone activity (GO:0005179), extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), heparin binding (GO:0008201), extracellular matrix constituent conferring elasticity (GO:0030023), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (6): microfibril (GO:0001527), extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Extracellular matrix organization	3
Elastic fibre formation	1
Signaling by TGF-beta Receptor Complex	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
eye morphogenesis	2
extracellular matrix	2
binding	2
system development	1
kidney development	1
hexose metabolic process	1
circulatory system development	1
macromolecule biosynthetic process	1
cell adhesion	1
carbohydrate homeostasis	1
eye development	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
embryonic organ morphogenesis	1
lung development	1
anatomical structure development	1
cellular response to growth factor stimulus	1
response to transforming growth factor beta	1
cellular response to peptide hormone stimulus	1
osteoclast development	1
negative regulation of osteoclast differentiation	1
regulation of osteoclast development	1
renal system development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
respiratory tube development	1
respiratory system development	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
receptor ligand activity	1
structural molecule activity	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1

Protein interactions and networks

STRING

3522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBN1	ELN	P15502	999
FBN1	ADAMTS10	Q9H324	995
FBN1	MFAP2	P55001	993
FBN1	LTBP1	P22064	984
FBN1	FN1	P02751	973
FBN1	FBLN2	P98095	954
FBN1	ADAMTSL4	Q6UY14	940
FBN1	MFAP5	Q13361	939
FBN1	COL3A1	P02461	932
FBN1	TGFBR1	P36897	924
FBN1	TGFBR2	P37173	905
FBN1	COL1A2	P02464	891
FBN1	MFAP1	P55081	885
FBN1	FBLN5	Q9UBX5	884
FBN1	TGFB1	P01137	877

IntAct

79 interactions, top by confidence:

A	B	Type	Score
FBN1	FBN1	psi-mi:“MI:0407”(direct interaction)	0.800
FBN1	FBN1	psi-mi:“MI:1127”(putative self interaction)	0.800
rep	GTF2F2	psi-mi:“MI:0914”(association)	0.730
LOX	EFEMP2	psi-mi:“MI:0915”(physical association)	0.730
EFEMP2	LOX	psi-mi:“MI:0915”(physical association)	0.730
ELN	EFEMP2	psi-mi:“MI:0915”(physical association)	0.650
FBN1	EFEMP2	psi-mi:“MI:0407”(direct interaction)	0.610
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
FBN1	GET4	psi-mi:“MI:0915”(physical association)	0.560
FBN1	SGTB	psi-mi:“MI:0915”(physical association)	0.560
HGS	FBN1	psi-mi:“MI:0915”(physical association)	0.560
LOX	FBN1	psi-mi:“MI:0407”(direct interaction)	0.540
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
ELN	FBN1	psi-mi:“MI:0915”(physical association)	0.520
MFAP4	FBN1	psi-mi:“MI:0915”(physical association)	0.490
FBN1	MFAP4	psi-mi:“MI:0915”(physical association)	0.490
LTBP1	FBN1	psi-mi:“MI:0407”(direct interaction)	0.440
FBN1	LTBP4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (39): FBN1 (Affinity Capture-MS), FBN1 (Affinity Capture-MS), FBN1 (Affinity Capture-MS), FBN1 (Affinity Capture-MS), FBN1 (Affinity Capture-RNA), FBN1 (Affinity Capture-MS), HGS (Two-hybrid), SGTB (Two-hybrid), GET4 (Two-hybrid), MFAP2 (Reconstituted Complex), FBN1 (Reconstituted Complex), FBN1 (Reconstituted Complex), FBN1 (Reconstituted Complex), FBN1 (Affinity Capture-MS), FBN1 (Reconstituted Complex)

ESM2 similar proteins: A0A6I8RMG7, A2A863, A2VCU8, A7E2Z9, P01130, P01131, P04412, P0CY46, P16144, P18563, P18564, P24043, P35555, P35950, P35952, P35953, P98133, P98155, P98156, P98165, P98166, Q1RPR6, Q28832, Q2KIT5, Q3UZV7, Q4G063, Q4V7M2, Q5XH36, Q60438, Q61220, Q61554, Q62918, Q64632, Q6AYF4, Q6DDW2, Q6UXH1, Q7SXF6, Q7ZXL5, Q863C4, Q8CFM6

Diamond homologs: A0A1D5NSM8, A1A5Y0, A2AVA0, A2RUV0, A2VCU8, A5A8Y8, A6QR11, B3EWY9, B5DFC9, G3I6Z6, O75095, O88322, P07996, P0C6B8, P10493, P12105, P14585, P21783, P35441, P35448, P35555, P35556, P41990, P46531, P82279, P98133, Q01705, Q07008, Q14112, Q20911, Q28178, Q2PC93, Q2TAL6, Q2VWQ2, Q3U515, Q4LDE5, Q5R3Z7, Q5RBP1, Q61220, Q61554

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
FBN1	“down-regulates activity”	EFEMP2	binding
FBN1	“up-regulates quantity by expression”	MMP1	“transcriptional regulation”
FBN1	“up-regulates quantity”	TGFB1	binding
FBN1	“up-regulates activity”	SMAD2
IL1A	“down-regulates quantity by repression”	FBN1	“transcriptional regulation”
LTBP2	“up-regulates activity”	FBN1	binding
“all-cis-5,8,11,14,17-icosapentaenoic acid”	“up-regulates quantity by expression”	FBN1
FBN1	“down-regulates activity”	FBLN5	binding
WNT3A	“up-regulates quantity by stabilization”	FBN1
IGF1	“up-regulates quantity by expression”	FBN1	“transcriptional regulation”
IGF1R	“up-regulates quantity by expression”	FBN1	“transcriptional regulation”
DCN	“up-regulates quantity by expression”	FBN1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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
Molecules associated with elastic fibres	8	63.3×	1e-10
Elastic fibre formation	7	60.3×	3e-09
Extracellular matrix organization	6	9.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of gene expression	9	7.3×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

9261 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2056
Likely pathogenic	1124
Uncertain significance	2682
Likely benign	1928
Benign	162

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013590	NM_000138.5(FBN1):c.5196del (p.Cys1733fs)	Pathogenic
1013603	NM_000138.5(FBN1):c.4878del (p.Phe1626fs)	Pathogenic
1014036	NM_000138.5(FBN1):c.5095T>A (p.Tyr1699Asn)	Pathogenic
1018383	NM_000138.5(FBN1):c.169A>G (p.Asn57Asp)	Pathogenic
1060002	NM_000138.5(FBN1):c.5174T>A (p.Ile1725Asn)	Pathogenic
1068546	NM_000138.5(FBN1):c.7409_7410delinsAT (p.Cys2470Tyr)	Pathogenic
1068666	NM_000138.5(FBN1):c.6564_6565insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCGATTGGAGGTTTT (p.Glu2189delinsPhePhePhePhePhePheXaaXaaXaaXaaValSerProPheTer)	Pathogenic
1068667	NM_000138.5(FBN1):c.127A>T (p.Lys43Ter)	Pathogenic
1068676	NM_000138.5(FBN1):c.6253T>G (p.Cys2085Gly)	Pathogenic
1068829	NM_000138.5(FBN1):c.2764A>T (p.Lys922Ter)	Pathogenic
1069308	NM_000138.5(FBN1):c.8118del (p.Asp2706fs)	Pathogenic
1069359	NM_000138.5(FBN1):c.7382dup (p.Asn2461fs)	Pathogenic
1069382	NM_000138.5(FBN1):c.6793T>A (p.Cys2265Ser)	Pathogenic
1069383	NM_000138.5(FBN1):c.6769_6773del (p.Asp2257fs)	Pathogenic
1069412	NM_000138.5(FBN1):c.5716del (p.Arg1906fs)	Pathogenic
1069595	NM_000138.5(FBN1):c.4942+2T>C	Pathogenic
1069625	NM_000138.5(FBN1):c.5066-1G>T	Pathogenic
1069627	NM_000138.5(FBN1):c.8016_8017insAG (p.Gly2673fs)	Pathogenic
1069628	NM_000138.5(FBN1):c.4382G>A (p.Cys1461Tyr)	Pathogenic
1069717	NM_000138.5(FBN1):c.3583del (p.Cys1195fs)	Pathogenic
1069718	NM_000138.5(FBN1):c.3511T>C (p.Cys1171Arg)	Pathogenic
1069719	NM_000138.5(FBN1):c.3116G>A (p.Cys1039Tyr)	Pathogenic
1069830	NC_000015.9:g.(?48902915)(48905299_?)del	Pathogenic
1069831	NC_000015.9:g.(?48703181)(48744887_?)del	Pathogenic
1069957	NM_000138.5(FBN1):c.3906dup (p.Phe1303fs)	Pathogenic
1070664	NM_000138.5(FBN1):c.1540C>T (p.Gln514Ter)	Pathogenic
1070938	NM_000138.5(FBN1):c.4491C>A (p.Cys1497Ter)	Pathogenic
1070993	NM_000138.5(FBN1):c.3929dup (p.Tyr1311fs)	Pathogenic
1071108	NM_000138.5(FBN1):c.300C>A (p.Cys100Ter)	Pathogenic
1071312	NM_000138.5(FBN1):c.8057G>T (p.Cys2686Phe)	Pathogenic

SpliceAI

7879 predictions. Top by Δscore:

Variant	Effect	Δscore
15:48411375:TGATC:T	acceptor_gain	1.0000
15:48411376:GATC:G	acceptor_gain	1.0000
15:48411378:TC:T	acceptor_gain	1.0000
15:48411378:TCC:T	acceptor_loss	1.0000
15:48411379:CC:C	acceptor_gain	1.0000
15:48411379:CCTGG:C	acceptor_loss	1.0000
15:48411380:C:CC	acceptor_gain	1.0000
15:48415534:AC:A	donor_gain	1.0000
15:48415535:CC:C	donor_gain	1.0000
15:48416782:A:C	donor_gain	1.0000
15:48420684:TGCCA:T	donor_gain	1.0000
15:48420804:CGT:C	acceptor_gain	1.0000
15:48420807:C:CC	acceptor_gain	1.0000
15:48421683:TTATC:T	acceptor_loss	1.0000
15:48421685:ATC:A	acceptor_loss	1.0000
15:48421686:TCTAT:T	acceptor_loss	1.0000
15:48421687:C:CA	acceptor_loss	1.0000
15:48421687:C:CC	acceptor_gain	1.0000
15:48421688:T:A	acceptor_loss	1.0000
15:48421948:TCACC:T	donor_loss	1.0000
15:48421949:CA:C	donor_loss	1.0000
15:48421950:A:AC	donor_gain	1.0000
15:48421950:A:AG	donor_loss	1.0000
15:48421951:C:CT	donor_gain	1.0000
15:48421951:CCA:C	donor_gain	1.0000
15:48422064:AAGAT:A	acceptor_gain	1.0000
15:48422065:AGAT:A	acceptor_gain	1.0000
15:48422066:GAT:G	acceptor_gain	1.0000
15:48422067:AT:A	acceptor_gain	1.0000
15:48422069:C:CC	acceptor_gain	1.0000

AlphaMissense

19195 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:48420692:C:G	C2605S	1.000
15:48420693:A:G	C2605R	1.000
15:48420693:A:T	C2605S	1.000
15:48420700:C:A	W2602C	1.000
15:48420700:C:G	W2602C	1.000
15:48420732:A:G	C2592R	1.000
15:48420738:A:G	C2590R	1.000
15:48420764:C:G	C2581S	1.000
15:48420765:A:G	C2581R	1.000
15:48420765:A:T	C2581S	1.000
15:48420776:C:G	C2577S	1.000
15:48420777:A:G	C2577R	1.000
15:48420777:A:T	C2577S	1.000
15:48421991:A:G	C2511R	1.000
15:48422022:A:C	C2500W	1.000
15:48422023:C:G	C2500S	1.000
15:48422023:C:T	C2500Y	1.000
15:48422024:A:G	C2500R	1.000
15:48422024:A:T	C2500S	1.000
15:48422036:A:G	C2496R	1.000
15:48422056:C:G	C2489S	1.000
15:48422057:A:G	C2489R	1.000
15:48422057:A:T	C2489S	1.000
15:48425374:C:G	C2483S	1.000
15:48425375:A:G	C2483R	1.000
15:48425375:A:T	C2483S	1.000
15:48425414:A:G	C2470R	1.000
15:48425447:A:G	C2459R	1.000
15:48425816:C:G	C2418S	1.000
15:48425817:A:T	C2418S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000323 (15:48579032 A>G), RS1000006410 (15:48631137 T>A,C), RS1000009342 (15:48488435 G>A,C), RS1000012258 (15:48647195 T>C), RS1000038010 (15:48443859 C>T), RS1000042233 (15:48526712 G>A,C), RS1000082721 (15:48488316 A>C), RS1000092204 (15:48414392 G>A), RS1000095191 (15:48622638 T>C), RS1000095554 (15:48532582 A>C,G), RS1000109645 (15:48558440 T>A), RS1000121004 (15:48477985 G>A), RS1000130553 (15:48540751 C>A,T), RS1000132471 (15:48418593 T>C), RS1000140277 (15:48513838 C>T)

Disease associations

OMIM: gene MIM:134797 | disease phenotypes: MIM:154700, MIM:607086, MIM:102370, MIM:129600, MIM:184900, MIM:604308, MIM:608328, MIM:614185, MIM:616914, MIM:100800, MIM:233400, MIM:208085, MIM:231050, MIM:277600, MIM:609192, MIM:142623, MIM:142340, MIM:601144, MIM:174050, MIM:160700, MIM:177050, MIM:169300, MIM:121050, MIM:607087, MIM:611788, MIM:613680, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
Marfan syndrome	Definitive	Autosomal dominant
familial thoracic aortic aneurysm and aortic dissection	Definitive	Unknown
progeroid and marfanoid aspect-lipodystrophy syndrome	Strong	Autosomal dominant
Acromicric dysplasia	Strong	Autosomal dominant
stiff skin syndrome	Strong	Autosomal dominant
Weill-Marchesani syndrome 2, dominant	Strong	Autosomal dominant
isolated ectopia lentis	Supportive	Autosomal dominant
geleophysic dysplasia	Supportive	Autosomal dominant
neonatal Marfan syndrome	Supportive	Autosomal dominant
Weill-Marchesani syndrome	Supportive	Autosomal dominant
Shprintzen-Goldberg syndrome	Limited	Unknown
ectopia lentis 1, isolated, autosomal dominant	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Shprintzen-Goldberg syndrome	Disputed	AD
Marfan syndrome	Definitive	AD
familial thoracic aortic aneurysm and aortic dissection	Definitive	AD

Mondo (46): Marfan syndrome (MONDO:0007947), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Acromicric dysplasia (MONDO:0007055), ectopia lentis 1, isolated, autosomal dominant (MONDO:0007514), stiff skin syndrome (MONDO:0008492), MASS syndrome (MONDO:0011431), Weill-Marchesani syndrome 2, dominant (MONDO:0012013), geleophysic dysplasia 2 (MONDO:0013612), progeroid and marfanoid aspect-lipodystrophy syndrome (MONDO:0014831), connective tissue disorder (MONDO:0003900), achondroplasia (MONDO:0007037), Perrault syndrome 1 (MONDO:0009300), arthrogryposis, renal dysfunction, and cholestasis 1 (MONDO:0008822), geleophysic dysplasia (MONDO:0000127), Weill-Marchesani syndrome (MONDO:0018096)

Orphanet (27): Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Isolated ectopia lentis (Orphanet:1885), Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome (Orphanet:2084), Geleophysic dysplasia (Orphanet:2623), Stiff skin syndrome (Orphanet:2833), Progeroid and marfanoid aspect-lipodystrophy syndrome (Orphanet:300382), Acromicric dysplasia (Orphanet:969), Achondroplasia (Orphanet:15), Perrault syndrome (Orphanet:2855), Perrault syndrome type 1 (Orphanet:642945), Arthrogryposis-renal dysfunction-cholestasis syndrome (Orphanet:2697), Weill-Marchesani syndrome (Orphanet:3449), Familial aortic dissection (Orphanet:229)

HPO phenotypes

312 total (30 of 312 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000098	Tall stature
HP:0000160	Narrow mouth
HP:0000179	Thick lower lip vermilion
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000293	Full cheeks
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000079_2	Breast cancer	6.000000e-06
GCST001229_1	Thoracic aortic aneurysms and dissections	6.000000e-13
GCST003455_20	Spherical equivalent (joint analysis main effects and education interaction)	3.000000e-09
GCST003455_43	Spherical equivalent (joint analysis main effects and education interaction)	2.000000e-09
GCST003683_3	Intracranial, abdominal aortic or thoracic aortic aneurysm (pleiotropy)	1.000000e-08
GCST003944_40	Hepcidin/ferritin ratio	9.000000e-06
GCST004775_33	Pulse pressure	4.000000e-08
GCST005580_167	Intraocular pressure	1.000000e-08
GCST005667_36	Central corneal thickness	3.000000e-08
GCST006168_18	Pulse pressure x alcohol consumption interaction (2df test)	1.000000e-29
GCST006291_96	Spherical equivalent or myopia (age of diagnosis)	6.000000e-09
GCST006434_44	Systolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-12
GCST006976_57	Macular thickness	3.000000e-10
GCST007096_48	Pulse pressure	2.000000e-26
GCST007097_7	Pulse pressure	1.000000e-09
GCST007097_8	Pulse pressure	2.000000e-11
GCST007099_128	Systolic blood pressure	2.000000e-07
GCST007267_144	Systolic blood pressure	6.000000e-14
GCST007269_331	Pulse pressure	8.000000e-37
GCST008156_93	Hip circumference adjusted for BMI	7.000000e-06
GCST008839_246	Height	2.000000e-29
GCST008839_52	Height	4.000000e-23
GCST008839_522	Height	2.000000e-09
GCST010002_168	Refractive error	3.000000e-24
GCST010722_7	Spontaneous coronary artery dissection	2.000000e-09
GCST012226_361	Waist circumference adjusted for body mass index	4.000000e-13
GCST90000654_58	Central corneal thickness	8.000000e-10
GCST90002224_1	Height	9.000000e-11
GCST90020028_1883	Hip circumference adjusted for BMI	5.000000e-08
GCST90020029_291	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0007901	hepcidin:ferritin ratio
EFO:0005763	pulse pressure measurement
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0004329	alcohol drinking
EFO:0004847	age at onset
EFO:0006335	systolic blood pressure
EFO:0008039	BMI-adjusted hip circumference
EFO:0010820	spontaneous coronary artery dissection
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (28)

Descriptor	Name	Tree numbers
D000130	Achondroplasia	C05.116.099.343.110; C05.116.099.708.017; C16.320.240.500
D001014	Aortic Aneurysm	C14.907.055.239; C14.907.109.139
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D001022	Aortic Valve Insufficiency	C14.280.484.048.500
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D003240	Connective Tissue Diseases	C17.300
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D005660	Funnel Chest	C05.116.099.386; C05.660.386; C16.131.621.386
D006331	Heart Diseases	C14.280
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D007906	Lens Subluxation	C11.510.598
D055947	Loeys-Dietz Syndrome	C05.660.207.532; C14.907.055.239.587; C14.907.109.139.587; C16.131.077.537; C16.320.510
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D008944	Mitral Valve Insufficiency	C14.280.484.461
D008945	Mitral Valve Prolapse	C14.280.484.400.500
D009216	Myopia	C11.744.636
D012600	Scoliosis	C05.116.900.800.875
D056846	Weill-Marchesani Syndrome	C05.116.099.343.957; C11.270.921; C16.131.077.941; C16.320.290.842; C17.300.899
C535662	Acromicric dysplasia (supp.)
C562834	Aortic Aneurysm, Familial Thoracic 1 (supp.)
C564627	Aortic Aneurysm, Familial Thoracic 2 (supp.)
C567085	Aortic Aneurysm, Familial Thoracic 6 (supp.)
C536211	Congenital contractural arachnodactyly (supp.)
C536184	Familial ectopia lentis (supp.)
C536030	MASS syndrome (supp.)
C566112	Stiff Skin Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
sodium arsenite	affects methylation, decreases expression, affects cotreatment, increases abundance	4
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases expression	4
trichostatin A	decreases expression, affects cotreatment	3
Cyclosporine	decreases expression, increases expression	3
potassium chromate(VI)	decreases expression, affects cotreatment	2
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	2
entinostat	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Zoledronic Acid	increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cadmium	decreases expression, decreases reaction, increases abundance, increases palmitoylation	2
Copper	increases expression, affects binding	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1

Cellosaurus cell lines

84 cell lines: 51 finite cell line, 28 induced pluripotent stem cell, 3 embryonic stem cell, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5P79	GM13441	Finite cell line	Male
CVCL_9T88	chHES-419	Embryonic stem cell	Female
CVCL_A0KU	LANCEi020-A-10	Induced pluripotent stem cell	Male
CVCL_A0KX	LANCEi020-A-4	Induced pluripotent stem cell	Male
CVCL_A0KY	LANCEi020-A-5	Induced pluripotent stem cell	Male
CVCL_A0KZ	LANCEi020-A-6	Induced pluripotent stem cell	Male
CVCL_A0LA	LANCEi020-A-7	Induced pluripotent stem cell	Male
CVCL_A0LB	LANCEi020-A-8	Induced pluripotent stem cell	Male
CVCL_A0LC	LANCEi020-A-9	Induced pluripotent stem cell	Male
CVCL_A0ZZ	ZJUi005-A [Wrong name]	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01295047	PHASE4	COMPLETED	Comparison of Medical Therapies in Marfan Syndrome.
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT05353192	PHASE4	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone in Children With Achondroplasia
NCT00429364	PHASE3	COMPLETED	Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
NCT00485368	PHASE3	COMPLETED	Angiotensin Converting Enzyme Inhibitors in Marfan Syndrome
NCT00683124	PHASE3	UNKNOWN	Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
NCT00723801	PHASE3	COMPLETED	Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome
NCT00763893	PHASE3	TERMINATED	Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome
NCT00782327	PHASE3	COMPLETED	Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers
NCT01145612	PHASE3	UNKNOWN	Atenolol Versus Losartan in the Prevention of Progressive Dilation of the Aorta in Marfan Syndrome
NCT01361087	PHASE3	WITHDRAWN	Circulating Transforming Growth Factor Beta (TGF-β) in Individuals With Marfan Syndrome
NCT01715207	PHASE3	COMPLETED	Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT03197766	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT03424018	PHASE3	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT06164951	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Infigratinib in Children and Adolescents With Achondroplasia
NCT06926491	PHASE3	RECRUITING	Evaluate the Efficacy and Safety of KK8398 in Patients With Achondroplasia（AOBA Study）
NCT00593710	PHASE2	COMPLETED	Losartan Versus Atenolol for the Treatment of Marfan Syndrome
NCT00651235	PHASE2	UNKNOWN	A Randomized, Open-label, LOSARTAN Therapy on the Progression of Aortic Root Dilation in Patients With Marfan Syndrome
NCT01949233	PHASE2	UNKNOWN	The Oxford Marfan Trial
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies