GeneBe

KLHL24

protein-coding

kelch like family member 24, the group of BTB domain containing|Kelch like

Gene summary

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. [provided by RefSeq, Mar 2017]

MANE transcript

NM_017644.3

Inheritance

AR, AD

ClinVar variants

P:14U:95B:30

Top phenotype

Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr3:183,635,610-183,684,519

External References & Databases

Ensembl (ENSG00000114796)NCBI Gene (54800)OMIM (611295)HGNC:25947GenCCUniProt (Q6TFL4)AlphaFoldClinVar (KLHL24)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~48.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859372

Submitter: Ambry Genetics

cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859372

Submitter: Ambry Genetics

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: Ambry Genetics

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: Genomics England PanelApp

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: G2P

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: PanelApp Australia

cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859372

Submitter: PanelApp Australia

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: Ambry Genetics

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: Orphanet

cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859372

Submitter: Labcorp Genetics (formerly Invitae)

epidermolysis bullosa simplex 6, generalized, with scarring and hair lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015006

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005045

Submitter: ClinGen

KLHL24 was first reported in relation to autosomal recessive hypertrophic cardiomyopathy in 2019 (Hedberg-Oldfors et al., PMID: 30715372). Three variants (two nonsense and one missense) that have been reported in four probands across three publications (PMIDs: 30715372, 32870709, 36672924) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression data (PMID: 23715323). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on the meeting date 09/28/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesAD/AR

Manifestation: Cardiovascular; Dermatologic

Intervention: Cardiovascular

Rationale: The condition can involve severe, early-onset cardiomyopathy, and awareness may allow early interventions and management; heart transplant has been described

Refs: 27798626; 27889062; 29779254; 30226531; 30579426; 30715372; 31649980Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL24 variants in ClinVar

10 Conditions Cataloged
Inborn genetic diseasesTotal: 59
not providedTotal: 45
KLHL24-related disorderTotal: 37
not specifiedTotal: 24
Epidermolysis bullosa simplex 6, generalized, with scarring and hair lossTotal: 11
Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodiesTotal: 8
Epidermolysis bullosa simplex, Koebner typeTotal: 4
Hypertrophic cardiomyopathyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017644.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
23
clinvar
1
clinvar
 24
missense
1
clinvar
2
clinvar
88
clinvar
5
clinvar
1
clinvar
 97
nonsense
1
clinvar
2
clinvar
3
clinvar
 6
start loss
6
clinvar
 6
frameshift
1
clinvar
1
clinvar
2
clinvar
 4
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total9595282139

Highest pathogenic variant AF is 0.000006174381

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 146 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017644.3RefSeqNP_060114.26MANE Select
ENST00000242810.11EnsemblENSP00000242810.66MANE Select
NM_001349413.1RefSeqNP_001336342.17Standard
NM_001349414.1RefSeqNP_001336343.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • protein ubiquitination
  • intermediate filament organization
  • protein autoubiquitination
  • regulation of kainate selective glutamate receptor activity

Molecular Function

  • protein binding

Cellular Component

  • cytoplasm
  • adherens junction
  • desmosome
  • axon
  • Cul3-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000454652
Coding exons
6
Length
48910
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
125748
p
0.0000636
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.881903400.5600.00001873939
Missense (PolyPhen)46120.690.381141414
Synonymous0.05371171180.9940.000006231157
Loss of Function2.86924.20.3730.00000134306

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000620.000062rare
South Asian0.0000980.000098rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity (PubMed:27889062). As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation (PubMed:27798626). Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties (By similarity). {ECO:0000250|UniProtKB:Q56A24, ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}.;
Disease
DISEASE: Epidermolysis bullosa simplex, generalized, with scarring and hair loss (EBSSH) [MIM:617294]: A form of epidermolysis bullosa, a group of mechano-bullous disorders characterized by structural skin fragility, recurrent blister formation and erosion of the skin and mucous membranes occurring spontaneously or after mild trauma. Epidermolysis bullosa simplex is characterized by intraepidermal tissue separation that occurs within the basal keratinocytes at the bottom layer of epidermis. EBSSH is an autosomal dominant epidermolysis bullosa simplex, 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. {ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}. Note=The disease is caused by mutations 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. {ECO:0000269|PubMed:27798626}.;

Recessive Scores

pRec
0.113

Intolerance Scores

LoFtool
0.391
RVIS EVS
-0.78
RVIS percentile EVS
12.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.578

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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