KLHL24

Summary

KLHL24 (kelch like family member 24, HGNC:25947) is a protein-coding gene on chromosome 3q27.1, encoding Kelch-like protein 24 (Q6TFL4). Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity.

The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors.

Source: NCBI Gene 54800 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 141 total — 11 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_017644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25947
Approved symbol	KLHL24
Name	kelch like family member 24
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	DRE1, FLJ20059, KRIP6
Ensembl gene	ENSG00000114796
Ensembl biotype	protein_coding
OMIM	611295
Entrez	54800

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 62 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000242810, ENST00000427201, ENST00000437402, ENST00000454495, ENST00000454652, ENST00000461813, ENST00000468001, ENST00000468101, ENST00000473045, ENST00000475827, ENST00000476808, ENST00000481126, ENST00000482138, ENST00000492409, ENST00000493074, ENST00000853856, ENST00000853857, ENST00000853858, ENST00000853859, ENST00000853860, ENST00000853861, ENST00000853862, ENST00000853863, ENST00000853864, ENST00000853865, ENST00000853866, ENST00000853867, ENST00000853868, ENST00000853869, ENST00000853870, ENST00000853871, ENST00000853872, ENST00000853873, ENST00000853874, ENST00000853875, ENST00000853876, ENST00000853877, ENST00000921183, ENST00000943848, ENST00000943849, ENST00000943850, ENST00000943851, ENST00000943852, ENST00000943853, ENST00000943854, ENST00000943855, ENST00000943856, ENST00000943857, ENST00000943858, ENST00000943859, ENST00000943860, ENST00000943861, ENST00000943862, ENST00000943863, ENST00000943864, ENST00000943865, ENST00000943866, ENST00000943867, ENST00000943868, ENST00000943869, ENST00000943870, ENST00000943871, ENST00000943872, ENST00000943873, ENST00000943874, ENST00000943875

RefSeq mRNA: 17 — MANE Select: NM_017644 NM_001349413, NM_001349414, NM_001349415, NM_001349416, NM_001349417, NM_001349418, NM_001349419, NM_001349420, NM_001349421, NM_001349422, NM_001349423, NM_001349424, NM_001349425, NM_001349426, NM_001349428, NM_001349429, NM_017644

CCDS: CCDS3246

Canonical transcript exons

ENST00000242810 — 8 exons

Exon	Start	End
ENSE00001300733	183650296	183651276
ENSE00001368256	183635623	183635793
ENSE00001382038	183643480	183643542
ENSE00001878140	183679086	183684519
ENSE00003546311	183672296	183672484
ENSE00003655045	183663458	183663642
ENSE00003667695	183671034	183671222
ENSE00003679722	183664921	183665039

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.4820 / max 415.0215, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40110	34.3417	1805
40111	3.8074	1164
40112	0.3107	87
203047	0.0223	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.53	gold quality
blood vessel layer	UBERON:0004797	99.45	gold quality
buccal mucosa cell	CL:0002336	99.40	gold quality
sperm	CL:0000019	99.29	gold quality
cervix squamous epithelium	UBERON:0006922	99.22	silver quality
periodontal ligament	UBERON:0008266	99.16	silver quality
renal medulla	UBERON:0000362	98.46	gold quality
seminal vesicle	UBERON:0000998	98.26	gold quality
male germ cell	CL:0000015	98.18	gold quality
nipple	UBERON:0002030	98.09	gold quality
ventral tegmental area	UBERON:0002691	97.98	gold quality
pylorus	UBERON:0001166	97.84	gold quality
superior surface of tongue	UBERON:0007371	97.82	gold quality
inferior vagus X ganglion	UBERON:0005363	97.64	gold quality
cardia of stomach	UBERON:0001162	97.57	gold quality
corpus callosum	UBERON:0002336	97.49	gold quality
lateral globus pallidus	UBERON:0002476	97.43	gold quality
trigeminal ganglion	UBERON:0001675	97.40	gold quality
superior vestibular nucleus	UBERON:0007227	97.38	gold quality
subthalamic nucleus	UBERON:0001906	97.26	gold quality
pericardium	UBERON:0002407	97.10	gold quality
substantia nigra pars compacta	UBERON:0001965	97.07	gold quality
dorsal root ganglion	UBERON:0000044	97.04	gold quality
saphenous vein	UBERON:0007318	96.84	gold quality
globus pallidus	UBERON:0001875	96.81	gold quality
medulla oblongata	UBERON:0001896	96.80	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.71	gold quality
pharyngeal mucosa	UBERON:0000355	96.70	gold quality
medial globus pallidus	UBERON:0002477	96.59	gold quality
pons	UBERON:0000988	96.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	6.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO3

miRNA regulators (miRDB)

266 targeting KLHL24, 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-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5011-5P	100.00	83.46	5820
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-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642

Literature-anchored findings (GeneRIF, showing 12)

• KRIP6 regulates kainate receptors by inhibiting PICK1 modulation via competition or a mutual blocking effect (PMID:18692513)
• Data show that a miRNA, hsv1-mir-H27, encoded within the genome of herpes simplex virus 1 (HSV-1), targets the mRNA of the cellular transcriptional repressor Kelch-like 24 (KLHL24). (PMID:23512275)
• KLHL24 Mutation is associated with epidermolysis bullosa. (PMID:27798626)
• findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity (PMID:27889062)
• KLHL24 mutation is associated in the pathogenesis of skin abnormalities and epidermolysis bullosa simplex. (PMID:28532758)
• Study in a Dutch family propose that a KLHL24 mutation cause a syndromic rather than a skin-only type of epidermolysis bullosa, in which cardiomyopathy may be a dominant symptom. (PMID:29779254)
• Case Reports: Epidermolysis bullosa simplex -KLHL24 is characterized by congenital skin defects of the lower limbs, which heal rapidly, leaving hypopigmented-atrophic patches and peculiar stellate and linear raised scars. (PMID:30226531)
• we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM (PMID:30715372)
• Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy. (PMID:34740256)
• Keratin 14 Degradation and Aging in Epidermolysis Bullosa Simplex due to KLHL24 Gain-of-Function Variants. (PMID:35031308)
• A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation. (PMID:35975634)
• EBS in Children with De Novo Pathogenic Variants Disturbing Krt14. (PMID:38474236)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl24b	ENSDARG00000008275
danio_rerio	klhl24a	ENSDARG00000021739
mus_musculus	Klhl24	ENSMUSG00000062901
rattus_norvegicus	Klhl24	ENSRNOG00000033372

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), 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), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 24 — Q6TFL4 (reviewed: Q6TFL4)

Alternative names: Kainate receptor-interacting protein for GluR6, Protein DRE1

All UniProt accessions (9): Q6TFL4, C9J0A6, C9J2N4, C9J3M5, C9JCK3, C9JMQ9, C9JN72, C9JQ67, C9JXR5

UniProt curated annotations — full annotation on UniProt →

Function. Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity. As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation. Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties. Has a crucial role in cardiac development and function.

Subunit / interactions. Forms homodimers. Interacts with GRIK2. Component of the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24. Interacts with CUL3. Interacts with KRT14.

Subcellular location. Perikaryon. Cell projection. Axon. Cytoplasm. Cell junction. Desmosome. Adherens junction.

Tissue specificity. Expressed in the skin. Found in keratinocytes, dermal fibroblasts, and melanocytes. Basal-layer keratinocytes have lower KLHL24 expression than suprabasal keratinocytes. Expressed in the brain, spinal cord, liver, testis, heart and at higher levels in the skeletal muscle.

Post-translational modifications. Autoubiquitinated. Autoubiquitination leads to proteasomal degradation and is necessary to control KLHL24 levels.

Disease relevance. Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy (EBS6) [MIM:617294] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. EBS6 is an autosomal dominant disorder presenting at birth with extensive skin defects on the extremities, leaving behind hypopigmentation and atrophy with a whirled pattern. Cutaneous fragility and generalized blistering persist during childhood and decrease in adulthood. Adult patients have dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. The disease is caused by variants affecting the gene represented in this entry. Gain-of-function mutations that lead to excessive ubiquitination and degradation of KRT14 result in compromised mechanical integrity of basal keratinocytes. Under this pathological condition, trivial mechanical stress can induce blister formation at the basal layer of skin. Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (CMH29) [MIM:620236] A form of hypertrophic cardiomyopathy, a heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH29 is an autosomal recessive form associated with a poor prognosis due to lethal arrhythmias and cardiac failure. Cardiac muscle biopsies show intermyofibrillar accumulation of glycogen and polyglucosan bodies within cardiomyocytes. Intermyofibrillar glycogen accumulation is also present in skeletal muscle. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6TFL4-1	1	yes
Q6TFL4-2	2

RefSeq proteins (17): NP_001336342, NP_001336343, NP_001336344, NP_001336345, NP_001336346, NP_001336347, NP_001336348, NP_001336349, NP_001336350, NP_001336351, NP_001336352, NP_001336353, NP_001336354, NP_001336355, NP_001336357, NP_001336358, NP_060114* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030596	BTB_POZ_KLHL24	Domain
IPR047071	KLHL24_BACK	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (19 total): repeat 6, mutagenesis site 3, sequence conflict 3, domain 2, splice variant 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6TFL4-F1	87.69	0.73

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
32	increased protein stability.
90	weak interaction with cul3. weak autoubiquitination.
175	weak interaction with cul3. weak autoubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 343 (showing top): KOBAYASHI_EGFR_SIGNALING_24HR_UP, FREAC2_01, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, MENSE_HYPOXIA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, ATGTTAA_MIR302C, GTGCCTT_MIR506, FREAC3_01, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_PROTEIN_AUTOUBIQUITINATION, AAAGACA_MIR511

GO Biological Process (5): protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), intermediate filament organization (GO:0045109), protein autoubiquitination (GO:0051865), obsolete regulation of kainate selective glutamate receptor activity (GO:2000312)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), adherens junction (GO:0005912), desmosome (GO:0030057), axon (GO:0030424), Cul3-RING ubiquitin ligase complex (GO:0031463), perikaryon (GO:0043204), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell-cell junction	2
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
protein ubiquitination	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
neuron projection	1
cullin-RING ubiquitin ligase complex	1
neuronal cell body	1
cell junction	1

Protein interactions and networks

STRING

1226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL24	GRIK2	Q13002	841
KLHL24	CIAPIN1	Q6FI81	694
KLHL24	CUL3	Q13618	650
KLHL24	EXPH5	Q8NEV8	558
KLHL24	RBX1	P62877	550
KLHL24	CREBRF	Q8IUR6	518
KLHL24	LACTBL1	A8MY62	491
KLHL24	CHST7	Q9NS84	393
KLHL24	PNRC1	Q12796	393
KLHL24	DUSP5	Q16690	391
KLHL24	FBXO11	Q86XK2	391
KLHL24	FERMT1	Q9BQL6	376
KLHL24	YPEL2	Q96QA6	372
KLHL24	FBXO10	Q9UK96	371
KLHL24	LEMD3	Q9Y2U8	369

IntAct

76 interactions, top by confidence:

A	B	Type	Score
KLHL12	KLHL2	psi-mi:“MI:0914”(association)	0.850
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
KLHL24	CUL3	psi-mi:“MI:0914”(association)	0.730
STAMBP	PIK3C2A	psi-mi:“MI:0914”(association)	0.730
KEAP1	NFE2L1	psi-mi:“MI:0915”(physical association)	0.700
KLHL12	KLHL24	psi-mi:“MI:0915”(physical association)	0.670
CUL3	ENC1	psi-mi:“MI:0914”(association)	0.640
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	0.640
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
KLHL9	ENC1	psi-mi:“MI:0914”(association)	0.640
KLHL24	ATP6V1C2	psi-mi:“MI:0915”(physical association)	0.560
NCK2	KLHL24	psi-mi:“MI:0915”(physical association)	0.560
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
CUL3	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
RBM3	PRMT5	psi-mi:“MI:0914”(association)	0.530
RGS3	ZNF24	psi-mi:“MI:0914”(association)	0.530
DEF6	NFKB2	psi-mi:“MI:0914”(association)	0.530
PPP1R21	KLHL24	psi-mi:“MI:0915”(physical association)	0.500
APRT	KLHL24	psi-mi:“MI:0915”(physical association)	0.400
GSTZ1	KLHL24	psi-mi:“MI:0915”(physical association)	0.400
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
COPS5		psi-mi:“MI:0914”(association)	0.350
COPS6		psi-mi:“MI:0914”(association)	0.350
KLHL12	SKP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A2AUC9, B3DIV9, D2HEW7, D3ZA50, D3ZZC3, E9QJ30, G3X9X1, O14682, O35709, O60662, Q08BL9, Q0D2A9, Q1LYM6, Q2TBA0, Q2WGJ6, Q3B7M1, Q4KLM4, Q53GT1, Q56A24, Q5EB39, Q5RCQ9, Q5RDY3, Q5RGB8, Q5U504, Q5U575, Q5ZJU2, Q66HD2, Q6DEL7, Q6DFF7, Q6GQU2, Q6NYM1, Q6Q7X9, Q6TFL4, Q6V595, Q8BRG6, Q8BWA5, Q8CA72, Q8IY47, Q8N4N3

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
DNA Damage Recognition in GG-NER	5	23.8×	4e-04
Formation of TC-NER Pre-Incision Complex	5	17.6×	9e-04
Neddylation	13	10.3×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	5	51.4×	1e-05
protein neddylation	6	46.3×	2e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	10	5.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	4
Uncertain significance	67
Likely benign	11
Benign	23

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2443764	NM_017644.3(KLHL24):c.1048G>T (p.Glu350Ter)	Pathogenic
2443765	NM_017644.3(KLHL24):c.917G>A (p.Arg306His)	Pathogenic
2443766	KLHL24, 2T-G	Pathogenic
2443767	KLHL24, 1A-T	Pathogenic
264646	NM_017644.3(KLHL24):c.3G>A (p.Met1Ile)	Pathogenic
264647	NM_017644.3(KLHL24):c.3G>T (p.Met1Ile)	Pathogenic
264648	NM_017644.3(KLHL24):c.1A>G (p.Met1Val)	Pathogenic
370042	NM_017644.3(KLHL24):c.2T>C (p.Met1Thr)	Pathogenic
432253	NM_017644.3(KLHL24):c.1A>T (p.Met1Leu)	Pathogenic
4845247	NM_017644.3(KLHL24):c.532del (p.His178fs)	Pathogenic
931095	NM_017644.3(KLHL24):c.3G>C (p.Met1Ile)	Pathogenic
3362750	NM_017644.3(KLHL24):c.661C>T (p.Leu221Phe)	Likely pathogenic
3393173	NM_017644.3(KLHL24):c.1161G>A (p.Trp387Ter)	Likely pathogenic
4277719	NM_017644.3(KLHL24):c.450del (p.Leu151fs)	Likely pathogenic
4845246	NM_017644.3(KLHL24):c.1514A>G (p.Tyr505Cys)	Likely pathogenic

SpliceAI

1658 predictions. Top by Δscore:

Variant	Effect	Δscore
3:183643474:TTTTA:T	acceptor_loss	1.0000
3:183643475:TTTA:T	acceptor_loss	1.0000
3:183643476:TTAGG:T	acceptor_loss	1.0000
3:183643477:TA:T	acceptor_loss	1.0000
3:183643479:G:A	acceptor_loss	1.0000
3:183643539:AAAGG:A	donor_loss	1.0000
3:183643540:AAGG:A	donor_loss	1.0000
3:183643541:AG:A	donor_loss	1.0000
3:183643542:GGTAT:G	donor_loss	1.0000
3:183643543:GT:G	donor_loss	1.0000
3:183643544:T:G	donor_loss	1.0000
3:183663454:TTA:T	acceptor_loss	1.0000
3:183663455:TAG:T	acceptor_loss	1.0000
3:183663456:A:AC	acceptor_loss	1.0000
3:183663456:A:AG	acceptor_gain	1.0000
3:183663457:G:GG	acceptor_gain	1.0000
3:183663563:G:GT	donor_gain	1.0000
3:183663600:GA:G	donor_gain	1.0000
3:183663644:T:A	donor_loss	1.0000
3:183665040:G:GG	donor_gain	1.0000
3:183671029:TATA:T	acceptor_loss	1.0000
3:183671033:G:A	acceptor_loss	1.0000
3:183671033:GGT:G	acceptor_gain	1.0000
3:183671033:GGTAT:G	acceptor_gain	1.0000
3:183671219:TAAGG:T	donor_loss	1.0000
3:183671221:AGGT:A	donor_loss	1.0000
3:183671223:GT:G	donor_loss	1.0000
3:183671224:T:A	donor_loss	1.0000
3:183672292:TTA:T	acceptor_loss	1.0000
3:183672293:TA:T	acceptor_loss	1.0000

AlphaMissense

3954 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:183650535:G:C	R60P	1.000
3:183650555:G:C	D67H	1.000
3:183650555:G:T	D67Y	1.000
3:183650556:A:C	D67A	1.000
3:183650556:A:T	D67V	1.000
3:183650591:T:C	C79R	1.000
3:183650592:G:A	C79Y	1.000
3:183650593:C:G	C79W	1.000
3:183650598:G:C	R81T	1.000
3:183650599:A:C	R81S	1.000
3:183650599:A:T	R81S	1.000
3:183650607:T:A	L84H	1.000
3:183650607:T:C	L84P	1.000
3:183650618:A:C	S88R	1.000
3:183650620:C:A	S88R	1.000
3:183650620:C:G	S88R	1.000
3:183650627:T:C	F91L	1.000
3:183650628:T:C	F91S	1.000
3:183650629:C:A	F91L	1.000
3:183650629:C:G	F91L	1.000
3:183650637:T:C	M94T	1.000
3:183650638:G:A	M94I	1.000
3:183650638:G:C	M94I	1.000
3:183650638:G:T	M94I	1.000
3:183650639:T:C	F95L	1.000
3:183650640:T:C	F95S	1.000
3:183650641:T:A	F95L	1.000
3:183650641:T:G	F95L	1.000
3:183650676:T:A	V107D	1.000
3:183650790:T:C	L145P	1.000

dbSNP variants (sampled 300 via entrez): RS1000050874 (3:183652199 G>A), RS1000052911 (3:183659443 A>T), RS1000150379 (3:183676250 C>G,T), RS1000168445 (3:183672854 C>T), RS1000305126 (3:183677530 T>A), RS1000320004 (3:183666229 T>C), RS1000372815 (3:183653538 A>C,G), RS1000430434 (3:183672603 G>A), RS1000453252 (3:183657493 T>G), RS1000503733 (3:183657930 T>C), RS1000605388 (3:183664571 C>T), RS1000653982 (3:183676996 T>A), RS1000726361 (3:183635135 C>A), RS1000743714 (3:183678851 C>T), RS1000755625 (3:183677877 C>T)

Disease associations

OMIM: gene MIM:611295 | disease phenotypes: MIM:620236, MIM:617294, MIM:131900

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermolysis bullosa simplex 6, generalized, with scarring and hair loss	Strong	Autosomal dominant
cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies	Strong	Autosomal recessive
hypertrophic cardiomyopathy	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Moderate	AR

Mondo (5): cardiomyopathy (MONDO:0004994), cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (MONDO:0859372), epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (MONDO:0015006), hypertrophic cardiomyopathy (MONDO:0005045), epidermolysis bullosa simplex 1B, generalized intermediate (MONDO:0007554)

Orphanet (4): Rare cardiomyopathy (Orphanet:167848), Intermediate epidermolysis bullosa simplex with cardiomyopathy (Orphanet:508529), Rare hypertrophic cardiomyopathy (Orphanet:217569), Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form (Orphanet:79399)

HPO phenotypes

24 total (25 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001010	Hypopigmentation of the skin
HP:0001324	Muscle weakness
HP:0001596	Alopecia
HP:0001645	Sudden cardiac death
HP:0001653	Mitral regurgitation
HP:0001670	Asymmetric septal hypertrophy
HP:0001810	Dystrophic toenail
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002231	Sparse body hair
HP:0002293	Alopecia of scalp
HP:0003577	Congenital onset
HP:0004334	Dermal atrophy
HP:0007447	Diffuse palmoplantar hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0008401	Onychogryphosis of toenails
HP:0011462	Young adult onset
HP:0031319	Cardiomyocyte hypertrophy
HP:0031656	Systolic anterior motion of the mitral valve
HP:0032092	Left ventricular outflow tract obstruction
HP:0034386	Reduced left ventricular endsystolic diameter
HP:0034532	Increased myocardial glycogen content
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST008362_213	Birth weight	3.000000e-10
GCST010101_6	White matter hyperintensities	5.000000e-09
GCST010726_23	Periventricular white matter hyperintensities	6.000000e-08
GCST011946_31	White matter hyperintensity volume	8.000000e-14
GCST011947_47	White matter hyperintensity volume	1.000000e-12
GCST011949_16	White matter hyperintensity volume (adjusted for hypertension)	3.000000e-12
GCST011952_14	White matter hyperintensity volume x hypertension interaction (2df)	1.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	affects expression, increases expression, affects cotreatment	6
Valproic Acid	affects cotreatment, decreases expression, increases expression	6
trichostatin A	affects cotreatment, decreases expression, affects expression	4
cobaltous chloride	increases expression, affects cotreatment	4
bisphenol A	increases expression, decreases expression	3
sodium arsenite	increases expression, affects expression, decreases expression	3
Arsenic Trioxide	increases expression	3
Acetaminophen	affects expression, increases expression	3
didecyldimethylammonium	increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Tretinoin	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Sirolimus	affects cotreatment, affects expression, increases expression	2
GSK-J4	increases expression	1
afuresertib	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression, increases expression	1
alpha phellandrene	increases expression	1
propionaldehyde	decreases expression	1
dodecyldimethylamine oxide	increases expression	1
arsenite	decreases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
tri-o-cresyl phosphate	increases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1

Cellosaurus cell lines

10 cell lines: 8 induced pluripotent stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7QR	LUMCi045-A	Induced pluripotent stem cell	Male
CVCL_A7QS	LUMCi046-A	Induced pluripotent stem cell	Male
CVCL_A7RY	LUMCi045-A-1	Induced pluripotent stem cell	Male
CVCL_A7RZ	LUMCi046-A-1	Induced pluripotent stem cell	Male
CVCL_E2AL	HAP1 KLHL24 (-) 1	Cancer cell line	Male
CVCL_E2AM	HAP1 KLHL24 (-) 2	Cancer cell line	Male
CVCL_E3P9	LUMCi058-A	Induced pluripotent stem cell	Female
CVCL_E3PA	LUMCi058-A-1	Induced pluripotent stem cell	Female
CVCL_E3PB	LUMCi059-A	Induced pluripotent stem cell	Male
CVCL_E3PC	LUMCi059-A-1	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy