MAPKBP1

protein-coding

mitogen-activated protein kinase binding protein 1, the group of WD repeat domain containing

Gene summary

This gene encodes a scaffold protein that regulates the JNK (c-Jun N-terminal kinase) and NOD2 (nucleotide-binding oligomerization domain-containing protein 2) signaling pathways. The encoded protein interacts with another related JNK pathway scaffold protein, WDR62, via a conserved dimerization domain, and enhances JNK signaling. This protein may play a role in bacterial immunity by binding to the NOD2 receptor and negatively regulating downstream antibacterial and pro-inflammatory signaling. Mutations in this gene that impair cellular localization of the encoded protein cause a form of nephronophthisis, an autosomal-recessive kidney disorder, in human patients. [provided by RefSeq, May 2017]

MANE transcript

NM_014994.3

Inheritance

ClinVar variants

P:23U:267B:147

Top phenotype

Nephronophthisis 20

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr15:41,774,434-41,827,855

External References & Databases

Ensembl (ENSG00000137802)

Transcript & Mutation Effects

hg38 • Region Span ~53.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephronophthisis 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014997

Submitter: Labcorp Genetics (formerly Invitae)

nephronophthisis 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014997

Submitter: ClinGen

MAPKBP1 was first reported in relation to autosomal recessive nephronophthisis in 2017 (Maria et al., PMID: 28089251). Ten variants (nonsense, frameshift, missense) that have been reported in 11 probands in 4 publications (PMIDs: 28089251, 32505465, 33623699, 35140360) are included in this curation. All but two of the variants are null, indicating that this disease is largely caused by a loss-of-function mechanism. The maximum score for genetic evidence (12 pts.) was reached. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, functional alteration evidence; PMID: 28089251). Expression analysis showed that the encoded protein is expressed in tubular epithelial cells and glomeruli of the adult kidney. Analysis of inner medullary collecting duct cells shows increased DNA Damage Response signaling in mutants, consistent with the human phenotype. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic & Ciliopathy GCEP on 5/26/2021, and re-evaluated on 6/10/2024. Even though there was only one new case (PMID: 35140360) and no new experimental evidence, the panel felt that there was ample genetic evidence, with supporting functional evidence for many of the mutations, that outweighed the limited other experimental evidence. As a result of this reevaluation, the classification increased from Strong to Definitive supporting the relationship between MAPKBP1 and autosomal recessive nephronophthisis that has been demonstrated in both the research and clinical diagnostic settings, and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 6/10/2024 (SOP Version 10).

nephronophthisis 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009728

Submitter: Orphanet

nephronophthisis 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014997

Submitter: PanelApp Australia

late-onset nephronophthisisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019742

Submitter: Orphanet

Clinical Genomic Database (CGD)

Nephronophthisis 20AR

Manifestation: Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28089251

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAPKBP1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 311

Inborn genetic diseasesTotal: 197

MAPKBP1-related disorderTotal: 64

Nephronophthisis 20Total: 38

not specifiedTotal: 35

Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014994.3. 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			8 clinvar	106 clinvar	4 clinvar	118
missense	1 clinvar		249 clinvar	30 clinvar	7 clinvar	287
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss			1 clinvar			1
frameshift	1 clinvar	6 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	7 clinvar			15
Total	7	16	267	136	11	437

Highest pathogenic variant AF is 0.000013128873

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014994.3	RefSeq	NP_055809.2	30	MANE Select
ENST00000457542.7	Ensembl	ENSP00000397570.2	30	MANE Select
NM_001128608.2	RefSeq	NP_001122080.1	31	Standard
NM_001265611.2	RefSeq	NP_001252540.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of I-kappaB kinase/NF-kappaB signaling
negative regulation of defense response to bacterium
negative regulation of interleukin-8 secretion

Molecular Function

protein binding

Cellular Component

nucleus
cytoplasm
mitotic spindle pole

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000456763
Coding exons: 31
Length: 53422
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.37	693	892	0.777	0.0000521	9742
Missense (PolyPhen)		110	228.3	0.48181		2506
Synonymous	1.38	323	356	0.907	0.0000206	3154
Loss of Function	5.93	23	80.3	0.286	0.00000461	838

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00017	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00023	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negative regulator of NOD2 function. It down-regulates NOD2-induced processes such as activation of NF-kappa-B signaling, IL8 secretion and antibacterial response (PubMed:22700971). Involved in JNK signaling pathway (By similarity). {ECO:0000250|UniProtKB:Q6NS57, ECO:0000269|PubMed:22700971}.;
Disease: DISEASE: Nephronophthisis 20 (NPHP20) [MIM:617271]: A form of nephronophthisis, an autosomal recessive chronic tubulo- interstitial nephritis that progresses to end-stage renal failure. Some patients have cystic kidneys of normal size and no extrarenal manifestations, whereas others have enlarged renal size and severe extrarenal defects, including hypertrophic obstructive cardiomyopathy, aortic stenosis, pulmonary stenosis, patent ductus arteriosus, situs inversus, and periportal liver fibrosis. NPHP20 patients do not show extrarenal manifestations or evidence of a ciliopathy, such as situs inversus or polydactyly. {ECO:0000269|PubMed:28089251}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0907

Intolerance Scores

LoFtool: 0.520
RVIS EVS: -0.65
RVIS percentile EVS: 16.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.408

Gene Damage Prediction

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