KBTBD13

Summary

KBTBD13 (kelch repeat and BTB domain containing 13, HGNC:37227) is a protein-coding gene on chromosome 15q22.31, encoding Kelch repeat and BTB domain-containing protein 13 (C9JR72). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined.

Source: NCBI Gene 390594 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nemaline myopathy 6 (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 741 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 55
• MANE Select transcript: NM_001101362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37227
Approved symbol	KBTBD13
Name	kelch repeat and BTB domain containing 13
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	hCG_1645727, NEM6
Ensembl gene	ENSG00000234438
Ensembl biotype	protein_coding
OMIM	613727
Entrez	390594

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000432196

RefSeq mRNA: 1 — MANE Select: NM_001101362 NM_001101362

CCDS: CCDS45281

Canonical transcript exons

ENST00000432196 — 1 exons

Exon	Start	End
ENSE00001724191	65076746	65079948

Expression profiles

Bgee: expression breadth broad, 47 present calls, max score 86.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0312 / max 10.8695, expressed in 19 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147219	0.0312	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.10	gold quality
skeletal muscle tissue	UBERON:0001134	81.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.12	silver quality
apex of heart	UBERON:0002098	76.88	gold quality
muscle of leg	UBERON:0001383	74.06	gold quality
gastrocnemius	UBERON:0001388	72.81	gold quality
heart left ventricle	UBERON:0002084	71.05	gold quality
muscle tissue	UBERON:0002385	69.65	gold quality
popliteal artery	UBERON:0002250	66.62	gold quality
tibial artery	UBERON:0007610	66.60	gold quality
heart	UBERON:0000948	66.22	gold quality
right atrium auricular region	UBERON:0006631	65.77	gold quality
descending thoracic aorta	UBERON:0002345	60.86	gold quality
thoracic aorta	UBERON:0001515	53.54	gold quality
ascending aorta	UBERON:0001496	52.92	gold quality
left uterine tube	UBERON:0001303	49.27	gold quality
sural nerve	UBERON:0015488	47.76	gold quality
left coronary artery	UBERON:0001626	44.35	gold quality
fallopian tube	UBERON:0003889	44.20	gold quality
endocervix	UBERON:0000458	43.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	43.24	silver quality
body of uterus	UBERON:0009853	42.87	gold quality
uterine cervix	UBERON:0000002	42.41	gold quality
urinary bladder	UBERON:0001255	42.00	silver quality
bone marrow cell	CL:0002092	41.88	gold quality
right coronary artery	UBERON:0001625	41.82	gold quality
ectocervix	UBERON:0012249	41.81	gold quality
subcutaneous adipose tissue	UBERON:0002190	41.48	gold quality
colonic epithelium	UBERON:0000397	41.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting KBTBD13, 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-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-6814-5P	99.03	66.68	1273

Literature-anchored findings (GeneRIF, showing 5)

• mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families (PMID:21109227)
• these results demonstrate that KBTBD13 is a putative substrate adaptor for Cul3-RL that functions as a muscle specific ubiquitin ligase, and thereby implicate the ubiquitin proteasome pathway in the pathogenesis of KBTBD13-associated NEM. (PMID:22542517)
• KBTBD13 is an actin-binding protein that modulates muscle kinetics. (PMID:31671076)
• NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material. (PMID:33693846)
• KBTBD13 is a novel cardiomyopathy gene. (PMID:36335629)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	kbtbd13a	ENSDARG00000076449
mus_musculus	Kbtbd13	ENSMUSG00000054978

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Kelch repeat and BTB domain-containing protein 13 — C9JR72 (reviewed: C9JR72)

All UniProt accessions (1): C9JR72

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

Subunit / interactions. Component of the BCR(KBTBD13) E3 ubiquitin ligase complex, at least composed of CUL3 and KBTBD13 and RBX1. Interacts with CUL3.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in skeletal muscle.

Post-translational modifications. Autoubiquitinated.

Disease relevance. Nemaline myopathy 6 (NEM6) [MIM:609273] A form of nemaline myopathy characterized by childhood onset of slowly progressive proximal muscle weakness, exercise intolerance, and slow movements with stiff muscles. Patients are unable to run or correct themselves from falling over. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The BCB domain mediates the interaction with CUL3.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_001094832* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR052392	Kelch-BTB_domain-containing	Family

Pfam: PF00651, PF01344

UniProt features (10 total): repeat 5, sequence variant 3, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-C9JR72-F1	90.56	0.76

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 187 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, GOBP_SKELETAL_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_CONTRACTION, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_RELAXATION_OF_MUSCLE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOMF_ACTIN_BINDING

GO Biological Process (4): actin filament organization (GO:0007015), regulation of the force of skeletal muscle contraction (GO:0014728), protein ubiquitination (GO:0016567), relaxation of skeletal muscle (GO:0090076)

GO Molecular Function (2): actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
regulation of skeletal muscle contraction by chemo-mechanical energy conversion	1
protein modification by small protein conjugation	1
relaxation of muscle	1
actin binding	1
protein-containing complex binding	1
binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KBTBD13	TNNT1	P13805	932
KBTBD13	TPM2	P06468	897
KBTBD13	TPM3	P06753	884
KBTBD13	KLHL40	Q2TBA0	878
KBTBD13	NEB	P20929	862
KBTBD13	ACTA1	P02568	857
KBTBD13	CFL2	Q9Y281	822
KBTBD13	LMOD3	Q0VAK6	799
KBTBD13	CUL3	Q13618	725
KBTBD13	MYPN	Q86TC9	658
KBTBD13	CCDC78	A2IDD5	620
KBTBD13	MYOT	Q9UBF9	615
KBTBD13	MYO18B	Q8IUG5	598
KBTBD13	RYR1	P21817	561
KBTBD13	KLHDC1	Q8N7A1	531

IntAct

6 interactions, top by confidence:

A	B	Type	Score
KBTBD13	CUL3	psi-mi:“MI:0915”(physical association)	0.730
CUL3	KBTBD13	psi-mi:“MI:0407”(direct interaction)	0.730
KBTBD13	CUL3	psi-mi:“MI:0407”(direct interaction)	0.730

BioGRID (2): KBTBD13 (Proximity Label-MS), CUL3 (Affinity Capture-Western)

ESM2 similar proteins: A6NE02, A8MY62, C9JR72, D3Z7H8, D3ZU57, O09017, O15197, O19179, O95382, P0C0K6, P10588, P43136, P55203, Q02846, Q08DG4, Q15628, Q2KHV9, Q3U0S6, Q3UH93, Q5BK61, Q5U651, Q5W7P8, Q5ZMM1, Q6ZNJ1, Q6ZQA0, Q6ZVZ8, Q80ZD5, Q86WK7, Q8BH02, Q8BH83, Q8C828, Q8CIG9, Q8IUL8, Q8IYS2, Q8JGM4, Q8K2J9, Q8N239, Q8VHA6, Q91X21, Q96CD0

Diamond homologs: A0A1B8YAB1, A1YPR0, B0WWP2, B1H285, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D3Z8N4, E0CZ16, G3X9X1, O15062, O88939, O93567, O95365, P28575, P41182, P41183, Q08CL3, Q08DK3, Q13105, Q16RL8, Q2M0J9, Q3UQV5, Q52KB5, Q5EXX3, Q5R7B8, Q5RDY3, Q5TC79, Q5ZI33, Q5ZKD9, Q5ZM39, Q60821

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	464
Likely benign	159
Benign	35

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
31062	NM_001101362.3(KBTBD13):c.1222C>T (p.Arg408Cys)	Pathogenic
1709118	NM_001101362.3(KBTBD13):c.1170G>T (p.Lys390Asn)	Likely pathogenic
31061	NM_001101362.3(KBTBD13):c.1170G>C (p.Lys390Asn)	Likely pathogenic

SpliceAI

50 predictions. Top by Δscore:

Variant	Effect	Δscore
15:65077777:TG:T	donor_gain	0.5500
15:65077778:GG:G	donor_gain	0.5500
15:65077838:C:G	donor_gain	0.5400
15:65077487:G:GA	donor_gain	0.4600
15:65077987:G:T	donor_gain	0.4500
15:65077788:G:GG	donor_gain	0.4300
15:65077787:A:AG	donor_gain	0.4200
15:65077486:T:TA	donor_gain	0.3900
15:65077986:G:GT	donor_gain	0.3800
15:65077622:G:GT	donor_gain	0.3700
15:65077774:TGGTG:T	donor_gain	0.3300
15:65077775:GGTGG:G	donor_gain	0.3300
15:65077778:G:GT	donor_gain	0.3300
15:65077781:G:GG	donor_gain	0.3300
15:65077879:T:A	donor_gain	0.3300
15:65077884:C:A	donor_gain	0.3300
15:65077482:G:GT	donor_gain	0.3200
15:65077780:A:AG	donor_gain	0.3200
15:65077886:C:T	donor_gain	0.3200
15:65078006:G:GA	donor_gain	0.3200
15:65077783:ACGC:A	donor_gain	0.3100
15:65078017:A:AG	donor_gain	0.3100
15:65077856:G:GA	donor_gain	0.3000
15:65077821:C:G	donor_gain	0.2900
15:65077880:G:GA	donor_gain	0.2900
15:65078005:T:A	donor_gain	0.2900
15:65078033:C:A	donor_gain	0.2900
15:65077362:G:GT	donor_gain	0.2700
15:65077488:G:GG	donor_gain	0.2700
15:65077749:T:TA	acceptor_gain	0.2700

AlphaMissense

2920 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:65077374:T:A	W187R	0.992
15:65077374:T:C	W187R	0.992
15:65077376:G:C	W187C	0.992
15:65077376:G:T	W187C	0.992
15:65077889:C:A	N358K	0.992
15:65077889:C:G	N358K	0.992
15:65078023:T:A	V403D	0.992
15:65077905:T:C	F364L	0.991
15:65077907:C:A	F364L	0.991
15:65077907:C:G	F364L	0.991
15:65077950:T:A	W379R	0.989
15:65077950:T:C	W379R	0.989
15:65077449:T:G	Y212D	0.988
15:65077875:T:G	Y354D	0.988
15:65077291:C:A	A159D	0.987
15:65077670:G:C	W285C	0.987
15:65077670:G:T	W285C	0.987
15:65077906:T:G	F364C	0.987
15:65078076:T:A	W421R	0.987
15:65078076:T:C	W421R	0.987
15:65077453:T:A	I213N	0.986
15:65077979:C:A	N388K	0.986
15:65077979:C:G	N388K	0.986
15:65077836:A:C	S341R	0.985
15:65077838:C:A	S341R	0.985
15:65077838:C:G	S341R	0.985
15:65077885:G:C	R357P	0.984
15:65077888:A:T	N358I	0.984
15:65078103:T:C	F430L	0.984
15:65078105:C:A	F430L	0.984

dbSNP variants (sampled 300 via entrez): RS1000048869 (15:65075077 A>G,T), RS1000651112 (15:65075998 T>C), RS1000804949 (15:65080386 G>A), RS1001021711 (15:65075813 C>T), RS1002052042 (15:65076785 C>G,T), RS1002328838 (15:65075056 T>A), RS1002591118 (15:65075876 C>G,T), RS1002641714 (15:65077707 G>A,C), RS1002787310 (15:65079726 G>A), RS1002818615 (15:65079907 G>A), RS1003439253 (15:65074847 G>A), RS1003614549 (15:65078401 G>C), RS1004050576 (15:65078698 G>A), RS1004504480 (15:65077772 C>G,T), RS1004602137 (15:65077065 T>A,C)

Disease associations

OMIM: gene MIM:613727 | disease phenotypes: MIM:609273, MIM:161800, MIM:615083

GenCC curated gene-disease

Disease	Classification	Inheritance
nemaline myopathy 6	Definitive	Autosomal dominant
childhood-onset nemaline myopathy	Supportive	Autosomal dominant
hereditary peripheral neuropathy	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nemaline myopathy 6	Definitive	AD

Mondo (5): nemaline myopathy 6 (MONDO:0012237), congenital myopathy 2a, typical, autosomal dominant (MONDO:0008070), colorectal cancer, susceptibility to, 12 (MONDO:0014038), childhood-onset nemaline myopathy (MONDO:0015738), hereditary peripheral neuropathy (MONDO:0020127)

Orphanet (3): Childhood-onset nemaline myopathy (Orphanet:171439), Congenital myopathy with excess of thin filaments (Orphanet:98904), Attenuated familial adenomatous polyposis (Orphanet:220460)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000774	Narrow chest
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001533	Slender build
HP:0001561	Polyhydramnios
HP:0001623	Breech presentation
HP:0001638	Cardiomyopathy
HP:0001761	Pes cavus
HP:0001989	Fetal akinesia sequence
HP:0002067	Bradykinesia
HP:0002068	Neuromuscular dysphagia
HP:0002312	Clumsiness
HP:0002483	Bulbar signs
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002792	Reduced vital capacity

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C579880	Actin-Accumulation Myopathy (supp.)
C580202	Intranuclear Rod Myopathy (supp.)
C538398	Nemaline myopathy 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
abrine	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	increases expression	1
Thiram	increases expression	1
Triclosan	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03211923	Not specified	UNKNOWN	Muscle Relaxation in Myopathies With Positive Muscle Phenomena
NCT03278093	Not specified	UNKNOWN	Effect of Orthoses and Underfoot Vibration on Balance in Neuropathy