BBS4

Summary

BBS4 (Bardet-Biedl syndrome 4, HGNC:969) is a protein-coding gene on chromosome 15q24.1, encoding BBSome complex member BBS4 (Q96RK4). The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.

This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein’s shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein “BBSome” complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 585 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BBS4-related ciliopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 934 total — 74 pathogenic, 78 likely-pathogenic
• Phenotypes (HPO): 104
• MANE Select transcript: NM_033028

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:969
Approved symbol	BBS4
Name	Bardet-Biedl syndrome 4
Location	15q24.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000140463
Ensembl biotype	protein_coding
OMIM	600374
Entrez	585

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 11 protein_coding, 7 nonsense_mediated_decay, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000268057, ENST00000395205, ENST00000561914, ENST00000562084, ENST00000562219, ENST00000563600, ENST00000564239, ENST00000565160, ENST00000566197, ENST00000566400, ENST00000566829, ENST00000566938, ENST00000567279, ENST00000568535, ENST00000569001, ENST00000569151, ENST00000569338, ENST00000569440, ENST00000718296, ENST00000718297, ENST00000718298, ENST00000718299, ENST00000718300, ENST00000876645, ENST00000939792, ENST00000943719

RefSeq mRNA: 3 — MANE Select: NM_033028 NM_001252678, NM_001320665, NM_033028

CCDS: CCDS10246, CCDS58377

Canonical transcript exons

ENST00000268057 — 16 exons

Exon	Start	End
ENSE00003461796	72695177	72695228
ENSE00003463239	72735825	72735966
ENSE00003477175	72727940	72727994
ENSE00003497649	72736762	72736963
ENSE00003514016	72731305	72731457
ENSE00003537935	72715291	72715402
ENSE00003589007	72731555	72731726
ENSE00003604632	72686207	72686251
ENSE00003638798	72712244	72712307
ENSE00003667100	72735113	72735182
ENSE00003672370	72729616	72729684
ENSE00003687335	72716778	72716850
ENSE00003693151	72709700	72709779
ENSE00004034681	72722794	72722847
ENSE00004034689	72724528	72724655
ENSE00004034699	72737478	72738473

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 95.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1961 / max 250.4997, expressed in 1753 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147588	9.9067	1741
147587	1.2895	876

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.86	gold quality
oocyte	CL:0000023	95.17	gold quality
secondary oocyte	CL:0000655	94.41	gold quality
adenohypophysis	UBERON:0002196	92.63	gold quality
pituitary gland	UBERON:0000007	92.04	gold quality
right lobe of thyroid gland	UBERON:0001119	91.66	gold quality
ventricular zone	UBERON:0003053	91.61	gold quality
adrenal tissue	UBERON:0018303	91.40	gold quality
left ovary	UBERON:0002119	91.28	gold quality
left lobe of thyroid gland	UBERON:0001120	91.20	gold quality
right testis	UBERON:0004534	91.11	gold quality
left testis	UBERON:0004533	91.08	gold quality
right ovary	UBERON:0002118	90.87	gold quality
thyroid gland	UBERON:0002046	90.74	gold quality
endocervix	UBERON:0000458	90.67	gold quality
bronchial epithelial cell	CL:0002328	90.50	gold quality
tibial nerve	UBERON:0001323	90.39	gold quality
body of pancreas	UBERON:0001150	90.12	gold quality
testis	UBERON:0000473	89.54	gold quality
mucosa of stomach	UBERON:0001199	89.26	gold quality
right adrenal gland	UBERON:0001233	89.24	gold quality
right adrenal gland cortex	UBERON:0035827	89.00	gold quality
body of uterus	UBERON:0009853	88.88	gold quality
metanephros cortex	UBERON:0010533	88.64	gold quality
ovary	UBERON:0000992	88.59	gold quality
epithelium of bronchus	UBERON:0002031	88.51	gold quality
left adrenal gland	UBERON:0001234	88.49	gold quality
tibial artery	UBERON:0007610	88.25	gold quality
popliteal artery	UBERON:0002250	88.24	gold quality
ganglionic eminence	UBERON:0004023	88.23	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	279.69
E-ANND-3	yes	5.63
E-CURD-135	no	471.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting BBS4, 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-652-5P	99.91	67.49	505
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-3144-3P	98.15	67.34	677
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-630	97.50	66.38	921

Literature-anchored findings (GeneRIF, showing 15)

• BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. Evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening. (PMID:12016587)
• The phenotype of patients with BBS4 mutations consists of severe retinitis pigmentosa, variable obesity, brachydactyly with variable polydactyly, small or missing teeth, genital hypoplasia, and cardiovascular disease. (PMID:12365916)
• A novel Frameshift Mutation between the splice donor site and exon 5 of BBS4 in a Bardet-Biedl syndrome patient and a novel heterozygous base substitution in both an affected mother and her affected daughter. (PMID:12872256)
• BBS2 and BBS4 localized to cellular structures associated with motile cilia. (PMID:18299575)
• A novel missense mutation in BBS4 that co-segregates with Leber Congenital Amaurosis was identified in a consanguineous family from Saudi Arabia. (PMID:22219648)
• Ectopic expression of human BBS4 can rescue Bardet-Biedl syndrome phenotypes in Bbs4 null mice. (PMID:23554981)
• Findings indicate that Bbs proteins play a central role in the regulation of the actin cytoskeleton and control the cilia length through alteration of RhoA levels. (PMID:23716571)
• mediates endosomal recycling, sorting and signal transduction of Notch receptors (PMID:24681783)
• loss of BBS1, BBS4, or OFD1 led to decreased NF-kappaB activity and concomitant IkappaBbeta accumulation and that these defects were ameliorated with SFN treatment. (PMID:24691443)
• Results present evidence of a role for BBS4 in mediating the phosphorylation of TrkB by BDNF and its activation requires a proper localization to the ciliary axoneme. (PMID:24867303)
• a novel nonsense mutation in BBS4 gene in a Chinese family with Bardet-Biedl syndrome. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein; a rare heterozygous missense SNP in BBS10 gene was also detected (PMID:25533820)
• The BBSome assembly is spatially controlled by BBS1 and BBS4 in human cells. (PMID:32759308)
• BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response. (PMID:32894499)
• BBS4 protein has basal body/ciliary localization in sensory organs but extra-ciliary localization in oligodendrocytes during human development. (PMID:33860840)
• Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation. (PMID:33964006)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bbs4	ENSDARG00000063522
mus_musculus	Bbs4	ENSMUSG00000025235
rattus_norvegicus	Bbs4	ENSRNOG00000026171

Paralogs (14): IFT88 (ENSG00000032742), TTC7A (ENSG00000068724), TMTC4 (ENSG00000125247), TMTC1 (ENSG00000133687), TMTC3 (ENSG00000139324), TTC6 (ENSG00000139865), TTC13 (ENSG00000143643), OGT (ENSG00000147162), CFAP70 (ENSG00000156042), TTC8 (ENSG00000165533), TTC7B (ENSG00000165914), TTC16 (ENSG00000167094), TMTC2 (ENSG00000179104), TTC34 (ENSG00000215912)

Protein

Protein identifiers

BBSome complex member BBS4 — Q96RK4 (reviewed: Q96RK4)

Alternative names: Bardet-Biedl syndrome 4 protein

All UniProt accessions (11): Q96RK4, A0A0S2Z3A9, H3BN76, H3BPP7, H3BQV7, H3BRY9, H3BSE2, H3BSL2, H3BU58, H3BUQ7, H3BUU1

UniProt curated annotations — full annotation on UniProt →

Function. The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization. Required for microtubule anchoring at the centrosome but not for microtubule nucleation. May be required for the dynein-mediated transport of pericentriolar proteins to the centrosome.

Subunit / interactions. Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with PCM1 and DCTN1. Interacts with DC28B. Interacts with ALDOB and C2CD3. Interacts with PKD1. Interacts with CEP290. Interacts with DLEC1.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cell projection. Cilium membrane. Centriolar satellite. Cilium. Flagellum.

Tissue specificity. Ubiquitously expressed. The highest level of expression is found in the kidney.

Disease relevance. Bardet-Biedl syndrome 4 (BBS4) [MIM:615982] A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the BBS4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96RK4-1	1	yes
Q96RK4-2	2
Q96RK4-3	3

RefSeq proteins (3): NP_001239607, NP_001307594, NP_149017* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat

Pfam: PF13181, PF13414, PF13432

UniProt features (36 total): sequence variant 16, repeat 10, region of interest 5, compositionally biased region 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6XT9	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RK4-F1	78.36	0.59

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5620922	BBSome-mediated cargo-targeting to cilium
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 580 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_COGNITION, GOBP_PIGMENT_GRANULE_LOCALIZATION, GOBP_B_CELL_HOMEOSTASIS, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_BLOOD_PRESSURE

GO Biological Process (60): microtubule cytoskeleton organization (GO:0000226), mitotic cytokinesis (GO:0000281), neuron migration (GO:0001764), B cell homeostasis (GO:0001782), neural tube closure (GO:0001843), retina homeostasis (GO:0001895), heart looping (GO:0001947), negative regulation of systemic arterial blood pressure (GO:0003085), centrosome cycle (GO:0007098), spermatid development (GO:0007286), visual perception (GO:0007601), sensory perception of smell (GO:0007608), gene expression (GO:0010467), negative regulation of gene expression (GO:0010629), protein transport (GO:0015031), Wnt signaling pathway (GO:0016055), dendrite development (GO:0016358), regulation of lipid metabolic process (GO:0019216), ventricular system development (GO:0021591), striatum development (GO:0021756), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), adult behavior (GO:0030534), negative regulation of actin filament polymerization (GO:0030837), melanosome transport (GO:0032402), regulation of cytokinesis (GO:0032465), erythrocyte homeostasis (GO:0034101), microtubule anchoring at centrosome (GO:0034454), social behavior (GO:0035176), photoreceptor cell outer segment organization (GO:0035845), negative regulation of appetite by leptin-mediated signaling pathway (GO:0038108), positive regulation of multicellular organism growth (GO:0040018), fat cell differentiation (GO:0045444), photoreceptor cell maintenance (GO:0045494), positive regulation of cilium assembly (GO:0045724), retinal rod cell development (GO:0046548), brain morphogenesis (GO:0048854), sensory processing (GO:0050893), maintenance of protein location in nucleus (GO:0051457), regulation of stress fiber assembly (GO:0051492)

GO Molecular Function (6): protein-macromolecule adaptor activity (GO:0030674), dynactin binding (GO:0034452), alpha-tubulin binding (GO:0043014), beta-tubulin binding (GO:0048487), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (21): pericentriolar material (GO:0000242), photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), cilium (GO:0005929), motile cilium (GO:0031514), photoreceptor connecting cilium (GO:0032391), centriolar satellite (GO:0034451), BBSome (GO:0034464), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), ciliary membrane (GO:0060170), non-motile cilium (GO:0097730), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
cilium	6
microtubule organizing center	3
anatomical structure development	2
tubulin binding	2
centrosome	2
photoreceptor cell cilium	2
intracellular membraneless organelle	2
cytoskeleton organization	1
microtubule-based process	1
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
cell migration	1
generation of neurons	1
lymphocyte homeostasis	1
primary neural tube formation	1
tube closure	1
tissue homeostasis	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
cell cycle process	1
microtubule organizing center organization	1
germ cell development	1
spermatid differentiation	1
sensory perception of light stimulus	1
sensory perception of chemical stimulus	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
cell surface receptor signaling pathway	1
neuron projection development	1
lipid metabolic process	1
regulation of primary metabolic process	1

Protein interactions and networks

STRING

2318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BBS4	BBS9	P78514	999
BBS4	BBS2	Q9BXC9	999
BBS4	BBS7	Q8IWZ6	999
BBS4	BBS5	Q8N3I7	999
BBS4	BBS1	Q8NFJ9	999
BBS4	BBS10	Q8TAM1	949
BBS4	PCM1	Q15154	928
BBS4	BBS12	Q6ZW61	921
BBS4	TTC8	Q8TAM2	916
BBS4	RAB3IP	Q96QF0	914
BBS4	CCDC28B	Q9BUN5	873
BBS4	CEP290	O15078	864
BBS4	RAB8A	P24407	831
BBS4	DISC1	Q9NRI5	827
BBS4	DCTN1	Q14203	793

IntAct

162 interactions, top by confidence:

A	B	Type	Score
IQCB1	CEP290	psi-mi:“MI:0914”(association)	0.950
BBS1	BBS9	psi-mi:“MI:0914”(association)	0.940
BBS2	BBS9	psi-mi:“MI:0914”(association)	0.920
BBS1	BBS4	psi-mi:“MI:0915”(physical association)	0.920
BBS2	BBS9	psi-mi:“MI:0403”(colocalization)	0.920
BBS4	PCM1	psi-mi:“MI:0915”(physical association)	0.910
PCM1	BBS4	psi-mi:“MI:0915”(physical association)	0.910
PCM1	BBS4	psi-mi:“MI:0403”(colocalization)	0.910
BBS4	PCM1	psi-mi:“MI:0403”(colocalization)	0.910
BBS4	PCM1	psi-mi:“MI:0914”(association)	0.910
BBS7	BBS1	psi-mi:“MI:0914”(association)	0.910
BBS5	BBS9	psi-mi:“MI:0914”(association)	0.890
BBS9	BBS7	psi-mi:“MI:0914”(association)	0.860
BBS7	BBS9	psi-mi:“MI:0914”(association)	0.860
LZTFL1	BBS9	psi-mi:“MI:0914”(association)	0.850
BBS9	BBS4	psi-mi:“MI:0915”(physical association)	0.840

BioGRID (64): MYOG (Two-hybrid), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), PCM1 (Two-hybrid), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS), BBS4 (Affinity Capture-MS)

ESM2 similar proteins: A0MQH0, A4II29, A4IIX9, E9PTA2, O94826, P24786, Q0VC93, Q13507, Q16288, Q17QS6, Q25BN1, Q3ULA2, Q502M6, Q59H18, Q5GIG6, Q5IFJ9, Q5IS37, Q5IS82, Q5U5A6, Q5ZLX4, Q6DFV5, Q6GPR5, Q6GQW0, Q6TUI4, Q75Q39, Q7T3X9, Q7T3Y0, Q7TQP6, Q7Z6K4, Q7Z713, Q862Z2, Q8BPU7, Q8K4Q0, Q8N122, Q8VBX0, Q8WWX0, Q8WXK3, Q91987, Q91YD4, Q91ZA8

Diamond homologs: A1Z8E9, Q1JQ97, Q28G25, Q8C1Z7, Q96RK4, P39143, Q5CZ52, Q86TV6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BBS4	“form complex”	“BBsome complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 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
BBSome-mediated cargo-targeting to cilium	12	116.8×	6e-21
Cargo trafficking to the periciliary membrane	9	43.8×	3e-11
Cilium Assembly	13	27.7×	8e-14
Anchoring of the basal body to the plasma membrane	9	19.9×	3e-08
Organelle biogenesis and maintenance	13	16.8×	3e-11
Regulation of PLK1 Activity at G2/M Transition	5	12.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
melanosome transport	5	61.8×	3e-06
non-motile cilium assembly	8	37.5×	1e-08
cilium assembly	18	21.4×	9e-17
fat cell differentiation	7	20.5×	7e-06
axonogenesis	5	12.9×	3e-03
visual perception	8	10.3×	1e-04
protein transport	8	5.7×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	74
Likely pathogenic	78
Uncertain significance	319
Likely benign	333
Benign	32

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068968	NM_033028.5(BBS4):c.952C>T (p.Gln318Ter)	Pathogenic
1076608	NM_033028.5(BBS4):c.281del (p.Ala94fs)	Pathogenic
1076627	NC_000015.9:g.(?73004585)(73004648_?)del	Pathogenic
1172704	NM_033028.5(BBS4):c.187C>T (p.Gln63Ter)	Pathogenic
1324345	NM_033028.5(BBS4):c.1311_1312insT (p.Lys438Ter)	Pathogenic
1345413	NC_000015.9:g.(?73004565)(73009211_?)del	Pathogenic
1398623	NM_033028.5(BBS4):c.623T>A (p.Leu208Ter)	Pathogenic
1428249	NC_000015.9:g.(?73015115)(73024087_?)del	Pathogenic
1452272	NM_033028.5(BBS4):c.836_842del (p.Cys279fs)	Pathogenic
1456937	NC_000015.9:g.(?72978549)(73029948_?)del	Pathogenic
1606564	NM_033028.5(BBS4):c.332+8T>C	Pathogenic
1700584	NM_033028.5(BBS4):c.220G>A (p.Ala74Thr)	Pathogenic
1804844	NC_000015.9:g.(73002121_73004584)_(73004649_73007631)del	Pathogenic
1922198	NM_033028.5(BBS4):c.1083C>A (p.Tyr361Ter)	Pathogenic
2023901	NM_033028.5(BBS4):c.1016_1017del (p.Glu339fs)	Pathogenic
2060354	NM_033028.5(BBS4):c.640C>T (p.Gln214Ter)	Pathogenic
21729	NM_033028.5(BBS4):c.220+1G>C	Pathogenic
21730	NM_033028.5(BBS4):c.406-2A>C	Pathogenic
217435	NM_033028.5(BBS4):c.406-2A>G	Pathogenic
2177606	NM_033028.5(BBS4):c.780_781del (p.Arg260fs)	Pathogenic
2200217	NM_033028.5(BBS4):c.514dup (p.Ile172fs)	Pathogenic
2427093	NC_000015.9:g.(?72978569)(73009211_?)del	Pathogenic
2427094	NC_000015.9:g.(?73015115)(73020355_?)del	Pathogenic
2498298	NM_033028.5(BBS4):c.217del (p.Gln73fs)	Pathogenic
2501272	NC_000015.9:g.(72987570_73002040)_(73004649_73007631)del	Pathogenic
2502903	GRCh37/hg19 15q24.1(chr15:73000552-73006857)x1	Pathogenic
266087	NM_033028.5(BBS4):c.1226del (p.Ser409fs)	Pathogenic
266089	NM_033028.5(BBS4):c.172C>T (p.Gln58Ter)	Pathogenic
2680053	NM_033028.5(BBS4):c.31C>T (p.Gln11Ter)	Pathogenic
2700655	NM_033028.5(BBS4):c.346A>T (p.Lys116Ter)	Pathogenic

SpliceAI

2967 predictions. Top by Δscore:

Variant	Effect	Δscore
15:72709680:T:A	acceptor_gain	1.0000
15:72709684:A:AG	acceptor_gain	1.0000
15:72709685:A:AG	acceptor_gain	1.0000
15:72709686:A:G	acceptor_gain	1.0000
15:72709686:AATAT:A	acceptor_gain	1.0000
15:72709687:A:AG	acceptor_gain	1.0000
15:72709687:ATAT:A	acceptor_gain	1.0000
15:72709688:T:G	acceptor_gain	1.0000
15:72709689:A:AG	acceptor_gain	1.0000
15:72709689:AT:A	acceptor_gain	1.0000
15:72709689:ATGCT:A	acceptor_gain	1.0000
15:72709690:T:G	acceptor_gain	1.0000
15:72709690:T:TA	acceptor_gain	1.0000
15:72709693:T:A	acceptor_gain	1.0000
15:72709776:CAAGG:C	donor_loss	1.0000
15:72709777:AAGG:A	donor_loss	1.0000
15:72709778:AGGTA:A	donor_loss	1.0000
15:72709779:GGTAA:G	donor_loss	1.0000
15:72709780:G:T	donor_loss	1.0000
15:72715403:G:GG	donor_gain	1.0000
15:72716773:TACA:T	acceptor_loss	1.0000
15:72716775:CA:C	acceptor_loss	1.0000
15:72716776:A:AG	acceptor_gain	1.0000
15:72716776:AGATT:A	acceptor_loss	1.0000
15:72716777:G:GA	acceptor_gain	1.0000
15:72716777:GA:G	acceptor_gain	1.0000
15:72716777:GAT:G	acceptor_gain	1.0000
15:72716777:GATT:G	acceptor_gain	1.0000
15:72716777:GATTT:G	acceptor_gain	1.0000
15:72716846:ATTGG:A	donor_gain	1.0000

AlphaMissense

3404 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:72709775:G:A	C51Y	0.999
15:72709776:C:G	C51W	0.999
15:72712307:G:C	A74P	0.999
15:72715291:C:A	A74E	0.999
15:72715326:T:C	S86P	0.999
15:72715327:C:T	S86F	0.999
15:72715393:C:A	A108D	0.999
15:72716783:T:C	L113P	0.999
15:72716803:G:C	A120P	0.999
15:72716804:C:A	A120D	0.999
15:72716824:G:C	A127P	0.999
15:72722812:G:A	G142R	0.999
15:72722812:G:C	G142R	0.999
15:72722813:G:A	G142E	0.999
15:72722818:T:C	C144R	0.999
15:72722819:G:A	C144Y	0.999
15:72722820:C:G	C144W	0.999
15:72724591:G:T	G175W	0.999
15:72724627:G:C	A187P	0.999
15:72724648:G:C	A194P	0.999
15:72727977:G:A	G209R	0.999
15:72727977:G:C	G209R	0.999
15:72727978:G:A	G209E	0.999
15:72729647:T:C	L225P	0.999
15:72729659:T:C	L229P	0.999
15:72731321:G:A	G243D	0.999
15:72731357:C:A	A255D	0.999
15:72731422:G:A	G277R	0.999
15:72731422:G:C	G277R	0.999
15:72731423:G:A	G277E	0.999

dbSNP variants (sampled 300 via entrez): RS1000022944 (15:72699796 C>T), RS1000088038 (15:72701280 G>A), RS1000104208 (15:72736399 G>A), RS1000149569 (15:72690734 A>G), RS1000175013 (15:72716663 G>A), RS1000282295 (15:72712715 C>G,T), RS1000337872 (15:72709934 T>C), RS1000361080 (15:72697124 G>A,C), RS1000369333 (15:72700255 GT>G,GTT), RS1000575205 (15:72730732 C>T), RS1000584382 (15:72686720 C>T), RS1000729487 (15:72722915 A>G), RS1000749200 (15:72723636 C>T), RS1000765122 (15:72725009 G>A), RS1000780436 (15:72718007 C>T)

Disease associations

OMIM: gene MIM:600374 | disease phenotypes: MIM:209900, MIM:615982, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
Bardet-Biedl syndrome 4	Definitive	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
BBS4-related ciliopathy	Definitive	AR

Mondo (5): Bardet-Biedl syndrome (MONDO:0015229), Bardet-Biedl syndrome 4 (MONDO:0014433), retinitis pigmentosa (MONDO:0019200), Bardet-Biedl syndrome 1 (MONDO:0008854), inherited retinal dystrophy (MONDO:0019118)

Orphanet (3): Bardet-Biedl syndrome (Orphanet:110), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000085	Horseshoe kidney
HP:0000100	Nephrotic syndrome
HP:0000107	Renal cyst
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000147	Polycystic ovaries
HP:0000163	Abnormal oral cavity morphology
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004557_28	Body mass index	1.000000e-08
GCST004558_25	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-08
GCST004559_21	Body mass index in physically active individuals	8.000000e-07
GCST005797_1	Theory of mind score in adolescence (Emotional Triangles Task)	9.000000e-07
GCST005956_11	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_52	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	5.000000e-07
GCST006613_120	Triglycerides	3.000000e-09
GCST008129_81	Body mass index	2.000000e-15
GCST90026415_6	Mild obesity-related type 2 diabetes	9.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0009103	theory of mind measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537909	Bardet-Biedl syndrome 1 (supp.)
C537912	Bardet-Biedl syndrome 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Doxorubicin	affects cotreatment, affects response to substance	2
Valproic Acid	decreases expression	2
Aflatoxin B1	increases expression	2
dicrotophos	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
(+)-JQ1 compound	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	increases expression	1
Cyclophosphamide	affects cotreatment, affects response to substance	1
Ethyl Methanesulfonate	increases expression	1
Fluorouracil	affects cotreatment, affects response to substance	1
Formaldehyde	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Dihydrotestosterone	increases expression	1
Testosterone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)