KLHL3

protein-coding

kelch like family member 3, the group of Kelch like|BTB domain containing|MicroRNA protein coding host genes

Gene 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]

MANE transcript

NM_017415.3

Inheritance

AR, AD, SD

ClinVar variants

P:41U:164B:37

Top phenotype

Pseudohypoaldosteronism, type IID

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr5:137,617,500-137,736,089

External References & Databases

Ensembl (ENSG00000146021)

Transcript & Mutation Effects

hg38 • Region Span ~118.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudohypoaldosteronism type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013781

Submitter: PanelApp Australia

pseudohypoaldosteronism type 2DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013781

Submitter: Ambry Genetics

pseudohypoaldosteronism type 2DDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0013781

Submitter: ClinGen

The KLHL3 gene is located on chromosome 5 at q31.2 and encodes kelch-like protein 3. KLHL3 is a substrate-specific adapter in the BCR E3 ubiquitination ligase complex which regulates ion transport in the distal nephron (Louis-Dit-Picard et al., PMID:22406640). The BCR complex mediates the ubiquitination of WNK4 and WNK1, activators of the OSR1/SPAK-NCC pathway which causes hypertension when overexpressed (Wakabayashi et al., PMID: 23453970). Pathogenic variation in KLHL3 impairs the ability of KLHL3 to bind to CUL3 and/or WNK4/1, leading to the misregulation of renal salt, K+, and H+ which ultimately causes PHAIID (Boyden et al., PMID: 22266938). KLHL3 was first reported in relation to semidominant pseudohypoaldosteronism type II D (PHAIID) in 2006 (Boyden et al., PMID: 22266938). 27 variants (missense, nonsense, and frameshift) that have been reported in 24 probands in one publication (PMIDs: 22266938) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by experimental evidence (animal models, expression studies, and in vitro functional assays; PMIDs: 22406640, 23387299, 23453970, 24821705, 28052936, 30148674). KLHL3 is expressed in the distal convoluting tubule and connecting tubule of the kidney, and is shown to interact with CUL3 and WNK4 which are both implicated in PHAII. The variant, R528H, along with multiple other variants (Ohta et al., PMID: 23387299) have extensive evidence of functional alteration in vitro and in vivo. Additionally, multiple mouse models show pathogenic variation in KLHL3 and KO in both heterozygous and homozygous mouse models phenocopying PHAIID and mirroring the reported molecular mechanism. In summary, KLHL3 is definitively associated with semidominant pseudohypoaldosteronism type II D. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 01/20/2022 (SOP Version 8).

pseudohypoaldosteronism type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013781

Submitter: Labcorp Genetics (formerly Invitae)

pseudohypoaldosteronism type 2DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013781

Submitter: Labcorp Genetics (formerly Invitae)

pseudohypoaldosteronism type 2DSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013781

Submitter: Orphanet

pseudohypoaldosteronism type 2DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013781

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Pseudohypoaldosteronism, type IIDAD/AR

Manifestation: Renal

Intervention: Renal

Rationale: Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective

Refs: 22266938

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL3 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 129

Pseudohypoaldosteronism type 2DTotal: 117

Inborn genetic diseasesTotal: 65

Pseudohypoaldosteronism type 2ATotal: 26

not specifiedTotal: 25

KLHL3-related disorderTotal: 16

Renal tubulopathiesTotal: 3

Cerebral palsyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017415.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	33 clinvar	4 clinvar	42
missense	13 clinvar	17 clinvar	156 clinvar			186
nonsense	4 clinvar	2 clinvar	1 clinvar			7
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	2 clinvar			5
Total	20	21	164	33	4	242

Highest pathogenic variant AF is 0.00001858812

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017415.3	RefSeq	NP_059111.2	15	MANE Select
ENST00000309755.9	Ensembl	ENSP00000312397.4	15	MANE Select
NM_001257194.1	RefSeq	NP_001244123.1	14	Standard
NM_001257195.2	RefSeq	NP_001244124.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation

Biological Process

ubiquitin-dependent protein catabolic process
protein ubiquitination
post-translational protein modification
ion homeostasis
selective autophagy

Molecular Function

actin binding
structural molecule activity
protein binding

Cellular Component

cytosol
cytoskeleton
Cul3-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309755
Coding exons: 15
Length: 118591
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.99	206	367	0.561	0.0000224	3862
Missense (PolyPhen)		61	148.48	0.41082		1420
Synonymous	0.751	134	146	0.921	0.00000957	1118
Loss of Function	4.35	5	31.2	0.160	0.00000141	366

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000090	0.0000088	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron (PubMed:14528312, PubMed:22406640, PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3) complex also mediates ubiquitination and degradation of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney (By similarity). {ECO:0000250|UniProtKB:E0CZ16, ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031}.;
Disease: DISEASE: Pseudohypoaldosteronism 2D (PHA2D) [MIM:614495]: A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive. {ECO:0000269|PubMed:22266938, ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:26435498, ECO:0000269|PubMed:27026694, ECO:0000269|PubMed:27780982, ECO:0000269|PubMed:28052936, ECO:0000269|PubMed:28511177}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.199
RVIS EVS: -0.87
RVIS percentile EVS: 10.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.818

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium