KYNU

protein-coding

kynureninase

Gene summary

Kynureninase is a pyridoxal-5'-phosphate (pyridoxal-P) dependent enzyme that catalyzes the cleavage of L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acids, respectively. Kynureninase is involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

MANE transcript

NM_003937.3

Inheritance

ClinVar variants

P:28U:79B:18

Top phenotype

Vertebral, cardiac, renal, and limb defects syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr2:142,877,657-143,055,833

External References & Databases

Ensembl (ENSG00000115919)

Transcript & Mutation Effects

hg38 • Region Span ~178.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vertebral, cardiac, renal, and limb defects syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060555

Submitter: PanelApp Australia

vertebral, cardiac, renal, and limb defects syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060555

Submitter: Labcorp Genetics (formerly Invitae)

encephalopathy due to hydroxykynureninuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009372

Submitter: Ambry Genetics

encephalopathy due to hydroxykynureninuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009372

Submitter: PanelApp Australia

encephalopathy due to hydroxykynureninuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009372

Submitter: Labcorp Genetics (formerly Invitae)

vertebral, cardiac, renal, and limb defects syndrome 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060555

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital vertebral-cardiac-renal anomalies syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020831

Submitter: Orphanet

encephalopathy due to hydroxykynureninuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009372

Submitter: Orphanet

vertebral, cardiac, renal, and limb defects syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060555

Submitter: ClinGen

*KYNU* was first reported in relation to autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 2 in 2017 (Shi H, et al., 2017, PMID: 28792876) but was previously identified with hydroxykynureninuria in 2007 (Christensen M, et al., 2007, PMID: 17334708). Congenital defects found in VCRL2 include segmentation defects, cardiac defects such as hypoplastic heart, hypoplastic kidneys, missing kidneys, clinodactyly, radial deviation, and polydactyly. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 14 unique variants (e.g. missense, nonsense, frameshift, splicing, and large deletion) have been reported in 11 probands from 5 publications (PMIDs: 28792876, 33942433, 31923704, 17334708, 34200361). Variants in this gene segregated with disease in 1 additional family member. The gene *KYNU* encodes Kynureninase, one of the enzymes responsible for the biosynthesis of NAD from Trpytophan. This gene-disease association is further supported by its biochemical function in the kynurenine pathway (PMID: 8706755) and a knockout mouse model (PMID: 28792876) which recapitulates the phenotype on a NAD-restricted diet. In summary, *KYNU* is definitively associated with autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 07/10/2020. It was reevaluated on 08/01/2022. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of 5 new cases (PMIDs: 33942433 and 34200361).

Clinical Genomic Database (CGD)

Vertebral, cardiac, renal, and limb defects syndrome 2AR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early identifcation and management

Refs: 17334708; 28792876; 34200361

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KYNU variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 84

not providedTotal: 31

Vertebral, cardiac, renal, and limb defects syndrome 2Total: 25

KYNU-related disorderTotal: 19

HydroxykynureninuriaTotal: 11

Congenital NAD deficiency disorderTotal: 9

Catel-Manzke syndromeTotal: 3

Paediatric disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003937.3. 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			1 clinvar	9 clinvar	3 clinvar	13
missense	3 clinvar	6 clinvar	72 clinvar	5 clinvar	1 clinvar	87
nonsense	1 clinvar	5 clinvar	1 clinvar			7
start loss						0
frameshift		7 clinvar				7
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	5 clinvar			11
Total	6	22	79	14	4	125

Highest pathogenic variant AF is 0.00015750766

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003937.3	RefSeq	NP_003928.1	13	MANE Select
ENST00000264170.9	Ensembl	ENSP00000264170.4	13	MANE Select
NM_001032998.2	RefSeq	NP_001028170.1	10	Standard
NM_001199241.2	RefSeq	NP_001186170.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tryptophan metabolism - Homo sapiens (human)
Tryptophan Metabolism
Selenium Micronutrient Network
NAD Biosynthesis II (from tryptophan)
Tryptophan metabolism

Biological Process

tryptophan catabolic process
aging
NAD biosynthetic process
tryptophan catabolic process to kynurenine
tryptophan catabolic process to acetyl-CoA

Molecular Function

pyridoxal phosphate binding
kynureninase activity
protein homodimerization activity
3-hydroxykynureninase activity

Cellular Component

nucleoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264170
Coding exons: 13
Length: 164824
Individuals with no LoFs: 125573
Homozygous LoFs: 0
Heterozygous LoFs: 175
Defined: 125748
p: 0.000696

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.413	267	249	1.07	0.0000126	3032
Missense (PolyPhen)		93	95.641	0.97239		1068
Synonymous	0.829	79	88.9	0.888	0.00000456	878
Loss of Function	0.0902	27	27.5	0.981	0.00000151	333

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00094	0.00092	rare
Latino/Admixed American	0.00022	0.00020	rare
Ashkenazi Jewish	0.00033	0.00030	rare
East Asian	0.00065	0.00065	rare
Finnish	0.00038	0.00037	rare
European (Non-Finnish)	0.0010	0.00098	notable
South Asian	0.00050	0.00046	rare
Other	0.00086	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3- hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3- hydroxyanthranilic acid (3-OHAA), respectively. Has a preference for the L-3-hydroxy form. Also has cysteine-conjugate-beta-lyase activity. {ECO:0000269|PubMed:11985583, ECO:0000269|PubMed:17300176, ECO:0000269|PubMed:28792876, ECO:0000269|PubMed:8706755, ECO:0000269|PubMed:9180257}.;
Disease: DISEASE: Hydroxykynureninuria (HYXKY) [MIM:236800]: An inborn error of amino acid metabolism characterized by massive urinary excretion of large amounts of kynurenine, 3-hydroxykynurenine and xanthurenic acid. Affected individuals manifest renal tubular dysfunction, metabolic acidosis, psychomotor retardation, non- progressive encephalopathy, and muscular hypertonia. {ECO:0000269|PubMed:17334708, ECO:0000269|PubMed:28792876}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vertebral, cardiac, renal, and limb defects syndrome 2 (VCRL2) [MIM:617661]: An autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and distal mild limb defects. {ECO:0000269|PubMed:28792876}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.539
RVIS EVS: -0.6
RVIS percentile EVS: 18.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.876

Gene Damage Prediction

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