KLHL3 kelch like family member 3 [Homo sapiens (human)] - Gene

Summary

Official Symbol: KLHL3provided by HGNC
Official Full Name: kelch like family member 3provided by HGNC
Primary source: HGNC:HGNC:6354
See related: Ensembl:ENSG00000146021 MIM:605775; AllianceGenome:HGNC:6354
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PHA2D
Summary: This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]
Expression: Broad expression in thyroid (RPKM 5.9), heart (RPKM 4.0) and 23 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 5q31.2

Exon count:: 17

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	5	NC_000005.10 (137617500..137736089, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	5	NC_060929.1 (138138636..138261929, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	5	NC_000005.9 (136953189..137071778, complement)

Chromosome 5 - NC_000005.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway.
Title: KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway.
Kelch-like protein 3 in human disease and therapy.
Title: Kelch-like protein 3 in human disease and therapy.
Molecular dynamics simulations indicate the effects of these mutations on the interaction between the Kelch domain of kelch-like protein 3 (KLHL3) and the acidic motif (AM) of WNK lysine deficient protein kinase 4 protein (WNK4).
Title: Unveiling the Distinct Mechanisms by which Disease-Causing Mutations in the Kelch Domain of KLHL3 Disrupt the Interaction with the Acidic Motif of WNK4 through Molecular Dynamics Simulation.
The KLHL3 rs7444370 variant could be a protective factor in the pathogenesis of females' essential hypertension
Title: KLHL3 single-nucleotide polymorphism is associated with essential hypertension in Chinese Han population.
tacrolimus increases levels of KLHL3(S433-P), resulting in increased levels of WNK4, phosphorylated SPAK, and Na-Cl cotransporter.These findings demonstrate that KLHL3(S433-P) is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.
Title: Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.
A new recessive mutation in KLHL3 (S553L) was identified in familial hyperkalemia and hypertension. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form.
Title: Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter.
Mutation in the KLHL3 gene is associated with Gordon syndrome.
Title: Three cases of Gordon syndrome with dominant KLHL3 mutations.
The results demonstrate that Hcy decreases the expression of cMyBP-C through a KLHL3-mediated ubiquitin-proteasome pathway, and thereby influences heart development.
Title: cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases.
This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4
Title: Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study.
Data indicate that WNK lysine deficient protein kinase 4 protein (WNK4) was degraded not only by proteasomes but also by atypical protein kinase C scaffold protein p62 (p62)-kelch-like 3 protein (KLHL3)-mediated selective autophagy.
Title: Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation.

Submit: New GeneRIF Correction See all GeneRIFs (22)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Pseudohypoaldosteronism type 2D MedGen: C3469605 OMIM: 614495 GeneReviews: Pseudohypoaldosteronism Type II	not available
Pseudohypoaldosteronism, type 2 MedGen: C1449844 GeneReviews: Pseudohypoaldosteronism Type II	not available

EBI GWAS Catalog

Description
A genome-wide association study (GWAS) for bronchopulmonary dysplasia. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

L28232 (e-PCR)
- UniSTS:4889

AFM350yb1 (e-PCR)
- UniSTS:18484

RH101986 (e-PCR)
- UniSTS:96320

D5S1983 (e-PCR), detects polymorphism
- UniSTS:80017

EST179535 (e-PCR)
- UniSTS:62613

SGC32895 (e-PCR)
- UniSTS:81586

L28221 (e-PCR)
- UniSTS:19670

bac51504T (e-PCR)
- UniSTS:181471

L31431 (e-PCR)
- UniSTS:43759

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables actin binding	IEA Inferred from Electronic Annotation more info
enables cullin family protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables structural molecule activity	TAS Traceable Author Statement more info	PubMed
enables ubiquitin-like ligase-substrate adaptor activity	IBA Inferred from Biological aspect of Ancestor more info
enables ubiquitin-like ligase-substrate adaptor activity	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in distal tubule morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in gene expression	IEA Inferred from Electronic Annotation more info
involved_in macroautophagy	TAS Traceable Author Statement more info	PubMed
involved_in monoatomic ion homeostasis	IBA Inferred from Biological aspect of Ancestor more info
involved_in monoatomic ion homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in potassium ion homeostasis	IEA Inferred from Electronic Annotation more info
involved_in proteasome-mediated ubiquitin-dependent protein catabolic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in proteasome-mediated ubiquitin-dependent protein catabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in protein K48-linked ubiquitination	IDA Inferred from Direct Assay more info	PubMed
involved_in protein ubiquitination	IDA Inferred from Direct Assay more info	PubMed
involved_in protein ubiquitination	TAS Traceable Author Statement more info	PubMed
involved_in renal sodium ion absorption	IBA Inferred from Biological aspect of Ancestor more info
involved_in renal sodium ion absorption	IDA Inferred from Direct Assay more info	PubMed
involved_in renal sodium ion absorption	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in ubiquitin-dependent protein catabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in ubiquitin-dependent protein catabolic process	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
part_of Cul3-RING ubiquitin ligase complex	IBA Inferred from Biological aspect of Ancestor more info
part_of Cul3-RING ubiquitin ligase complex	IDA Inferred from Direct Assay more info	PubMed
part_of Cul3-RING ubiquitin ligase complex	TAS Traceable Author Statement more info	PubMed
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
located_in cytoskeleton	IEA Inferred from Electronic Annotation more info
is_active_in cytosol	IBA Inferred from Biological aspect of Ancestor more info
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info

General protein information

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Preferred Names: kelch-like protein 3

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_032569.1 RefSeqGene

Range

5002..123591

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001257194.1 → NP_001244123.1 kelch-like protein 3 isoform 2

See identical proteins and their annotated locations for NP_001244123.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks a 5' coding exon and has an alternate 5' exon which results in the use of a downstream in-frame start codon, compared to variant 1. These differences result in a protein (isoform 2; also known as KLHL3b) with a shorter N-terminus, compared to isoform 1.

Source sequence(s)

AB032955, AC106775, AF208070

Consensus CDS

CCDS58970.1

UniProtKB/Swiss-Prot

Q9UH77

Related

ENSP00000422099.1, ENST00000508657.5

Conserved Domains (4) summary

PHA03098
Location:15 → 534

PHA03098; kelch-like protein; Provisional

sd00038
Location:399 → 444

Kelch; KELCH repeat [structural motif]

cd18339
Location:1 → 117

BTB_POZ_KLHL3; BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in Kelch-like protein 3 (KLHL3)

cd18513
Location:115 → 244

BACK_KLHL3; BACK (BTB and C-terminal Kelch) domain found in Kelch-like protein 3 (KLHL3)
NM_001257195.2 → NP_001244124.1 kelch-like protein 3 isoform 3

See identical proteins and their annotated locations for NP_001244124.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks multiple 5' coding exons and has an alternate 5' exon which results in the use of a downstream in-frame start codon, compared to variant 1. These differences result in a protein (isoform 3; also known as KLHL3c) with a shorter N-terminus, compared to isoform 1. This isoform is predicted to lack the protein binding BTB domain that is present in isoform 1.

Source sequence(s)

AB032955, AC092318, AC106775, AF208069

Consensus CDS

CCDS58969.1

UniProtKB/Swiss-Prot

Q9UH77

Related

ENSP00000424828.1, ENST00000506491.5

Conserved Domains (3) summary

PHA03098
Location:15 → 484

PHA03098; kelch-like protein; Provisional

sd00038
Location:349 → 394

Kelch; KELCH repeat [structural motif]

cd18513
Location:65 → 194

BACK_KLHL3; BACK (BTB and C-terminal Kelch) domain found in Kelch-like protein 3 (KLHL3)
NM_017415.3 → NP_059111.2 kelch-like protein 3 isoform 1

See identical proteins and their annotated locations for NP_059111.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1; also known as KLHL3a).

Source sequence(s)

AB032955, AC106775, DA083147

Consensus CDS

CCDS4192.1

UniProtKB/Swiss-Prot

B2RBK7, Q9UH75, Q9UH76, Q9UH77, Q9ULU0, Q9Y6V6

Related

ENSP00000312397.4, ENST00000309755.9

Conserved Domains (4) summary

PHA03098
Location:47 → 566

PHA03098; kelch-like protein; Provisional

sd00038
Location:431 → 476

Kelch; KELCH repeat [structural motif]

cd18339
Location:29 → 149

BTB_POZ_KLHL3; BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in Kelch-like protein 3 (KLHL3)

cd18513
Location:147 → 276

BACK_KLHL3; BACK (BTB and C-terminal Kelch) domain found in Kelch-like protein 3 (KLHL3)