Alternative titles; symbols
HGNC Approved Gene Symbol: KYNU
SNOMEDCT: 17820009, 33116002, 72945002;
Cytogenetic location: 2q22.2 Genomic coordinates (GRCh38) : 2:142,877,664-143,055,833 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q22.2 | ?Hydroxykynureninuria | 236800 | Autosomal recessive | 3 |
| Vertebral, cardiac, renal, and limb defects syndrome 2 | 617661 | Autosomal recessive | 3 |
Kynureninase (EC 3.7.1.33) is a 3-hydroxykynureninase-type enzyme involved in the kynurenine pathway for the biosynthesis of NAD cofactors from tryptophan. It catalyzes the conversion of L-3-hydroxykynurenine and L-kynurenine to 3-hydroxyanthranilic acid and anthranilic acid, respectively. The reaction is pyridoxal-5-prime-dependent and is sensitive to nutritional vitamin B6 deprivation in mammals. Studies in mouse, rat, and pig suggest that kynureninase is a 95-kD kD homodimer predominantly located in the cytoplasm (Toma et al., 1997).
Kynureninase is also involved in the de novo NAD(H) synthesis pathway, using niacin from dietary input (summary by Shi et al., 2017).
Alberati-Giani et al. (1996) purified rat liver kynureninase and obtained amino acid sequence from tryptic peptides. Using a partial rat kidney cDNA cloned by degenerate RT-PCR to screen a human hepatoma cell cDNA library, they isolated a KYNU cDNA encoding a deduced 465-amino acid protein. Using the same approach, Toma et al. (1997) also isolated a human kynureninase cDNA clone. Human KYNU shares 48% and 85% amino acid identity with a putative yeast kynureninase and rat kynureninase, respectively. Both research groups identified a conserved lysine residue (lys276) thought to be the critical residue for cofactor binding within the pyridoxal-P-binding site consensus sequence. By Northern blot analysis, Alberati-Giani et al. (1996) detected strong expression of a 2-kb transcript in liver, placenta, and lung, with weaker expression in heart, brain, skeletal muscle, kidney, and pancreas. They also detected strong expression of a 2.6-kb transcript in placenta and liver, with weaker expression in heart, skeletal muscle, and pancreas. Using a recombinant kynureninase cDNA expressed in cell lines, Alberati-Giani et al. (1996) and Toma et al. (1997) observed kynureninase and hydroxykynureninase activity.
Elevated levels of kynureninase activity have been observed in cerebral and systemic inflammatory conditions (Heyes et al., 1993). A deficiency of kynureninase has been associated with abnormal tryptophan metabolism; see hydroxykynureninuria (236800).
Gross (2014) mapped the KYNU gene to chromosome 2q22.2 based on an alignment of the KYNU sequence (GenBank BC000879) with the genomic sequence (GRCh37).
Hydroxykynureninuria
Christensen et al. (2007) reported 2 brothers with a homozygous missense mutation (T198A; 605197.0001) in the KYNU gene. Both boys had high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin in urine (hydroxykynureninuria; 236800), but were otherwise well.
Vertebral, Cardiac, Renal, and Limb Defects Syndrome 2
In 2 unrelated children with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified homozygous or compound heterozygous truncating mutations in the KYNU gene (605197.0003-605197.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. Analysis of plasma from 1 patient (patient D) showed increased levels of the upstream metabolite 3HK and decreased levels of the downstream metabolites NAD and NAH(H). Studies in mice, which have different niacin levels compared to humans, indicated that the congenital malformations found in humans resulted from deficient NAD levels rather than increased 3HK levels. Shi et al. (2017) noted that NAD is a cofactor with broad cellular effects, including ATP production, macromolecular biosynthesis, redox reactions, energy metabolism, DNA repair, and modulation of transcription factors, all of which play an important role in embryogenesis. Shi et al. (2017) theorized that niacin supplementation could be of benefit in such patients.
In a 5-year-old girl with VCRL2 who was clinically diagnosed with Catel-Manzke syndrome (see 616145), Schule et al. (2021) identified homozygosity for deletion of exon 5 of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp (605197.0006), were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2.
In 4 unrelated patients with VCRL2, Szot et al. (2021) identified compound heterozygous or homozygous mutations in the KYNU gene (see, e.g., 605197.0007-605197.0010). Yeast with a homozygous knockout for bna5, the yeast ortholog of human KYNU, were transformed with plasmids containing KYNU with each of the mutations or with wildtype KYNU. Transfection with each of 4 mutant KYNU plasmids resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. NAD levels were reduced in the yeast transformed with any of the 6 mutant KYNU plasmids compared to wildtype. Szot et al. (2021) concluded that the compromised growth and/or NAD content of the bna5 knockout yeast transfected with each mutant KYNU was a result of impaired KYNU function.
Shi et al. (2017) found that Kynu-null mice were viable and normal. Plasma analysis showed increased 3HK levels, but normal NAD levels. The authors noted that mice have increased niacin levels compared to humans and that mouse embryos may receive niacin from their mothers, resulting in a buffering effect on genetic-based NAD deficiency. These findings suggested that the congenital malformations found in humans resulted from deficient NAD levels. Indeed, further studies in mutant mice born to mothers on a niacin-free diet showed that NAD deficiency due to lack of Kynu resulted in multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis. Supplementation of Kynu-null mouse embryos with niacin during gestation restored NAD levels and prevented the disruption of embryogenesis.
In a Somali boy, born to consanguineous parents, who was noted on urine metabolic screening to have high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin, characteristic of hydroxykynureninuria (236800), Christensen et al. (2007) identified homozygosity for a c.593A-T transversion in the KYNU gene, resulting in a thr198-to-ala (T198A) substitution. The patient presented with jaundice and vomiting at 9 days of age. He recovered in a matter of days and was well, with normal milestones and free from medication, at follow-up at age 6 years. This mutation was also found in homozygosity in the patient's brother, who also had high excretions of tryptophan metabolites. Both parents and 1 sib were heterozygous for the mutation; 2 remaining sibs did not carry the mutation.
This variant is classified as a variant of unknown significance because its contribution to essential hypertension (see 145500) has not been confirmed.
Zhang et al. (2011) studied a rare variant of KYNU that resulted in an arg188-to-gln substitution (R188Q), in relation to kynureninase activity and essential hypertension. A linkage peak for essential hypertension had been detected in the Han Chinese population (Zhu et al., 2001). Zhang et al. (2011) found that 33 of 1,124 Chinese patients with hypertension were heterozygous for R188Q, whereas only 14 of 1,084 normotensive controls were heterozygous for this mutation (188Q allele frequency, 0.015 vs 0.006; p = 0.0075). A genotype-discordant sib-pair study was performed in another 924 individuals from 213 families, indicating that 188Q carriers had higher systolic blood pressure (168.29 +/- 24.67 vs 139.00 +/- 12.82 mm Hg, p less than 0.001) and diastolic blood pressure (105.50 +/- 14.08 vs 90.75 +/- 11.07 mm Hg, p = 0.001) than did R188 homozygous sibs. The R188Q variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). Zhang et al. (2011) found that the kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (p less than 0.05). The kinetic Michaelis constant of 188Q carriers was lower than that of R188 homozygous subjects (0.05 +/- 0.02 vs 0.10 +/- 0.02 mmol/L, p = 0.005). R188Q mutation in vitro also showed less catalytic efficiency than the wildtype KYNU enzyme (maximal reaction velocity/kinetic Michaelis constant ratio, 0.050 +/- 0.012 vs 0.11 +/- 0.016 mL/min per mg; p = 0.029). Zhang et al. (2011) concluded that the rare KYNU variant R188Q affects kynureninase activity, and that their results are consistent with the hypothesis that this mutation can predispose to essential hypertension.
In a female infant (SCV000540921), born of consanguineous Lebanese parents (family C), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified a homozygous G-to-T transversion (c.170-1G-T) in intron 2 of the KYNU gene, resulting in a splice site alteration and premature termination (Val57GlufsTer21). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database and was classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutation essentially abolished KYNU enzymatic activity.
In a 3-year-old girl (SCV000540922), born of unrelated parents of North American origin (family D), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified compound heterozygous truncating mutations in the KYNU gene: a c.468T-A transversion in exon 6, resulting in a tyr156-to-ter (Y156X) substitution, and a 7-bp deletion (c.1045_1051delTTTAAGC; 605197.0005) in exon 13, resulting in a frameshift and premature termination (Phe349LysfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the ExAC database and were classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity.
For discussion of the 7-bp deletion (c.1045_1051del) in the KYNU gene, resulting in a frameshift and premature termination (Phe349LysfsTer4), that was found in compound heterozygous state in a patient (SCV000540923) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) by Shi et al. (2017), see 605197.0004.
In a 5-year-old girl with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) who was clinically diagnosed with Catel-Manzke syndrome (see 616145), Schule et al. (2021) identified homozygosity for deletion of exon 5 (EX5DEL) of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp, were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2. The patient had increased excretion of xanthurenic acid in her urine.
In a stillborn infant, born of consanguineous Sri Lankan parents (family 4), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified a homozygous c.788A-G transition (c.788A-G, NM_003937.3) in the KYNU gene, resulting in a his263-to-arg (H263R) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was not present in the gnomAD database. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the H263R mutation or with wildtype KYNU. The mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. The NAD level was also reduced in the yeast transformed with the mutant KYNU plasmid compared to wildtype.
In a patient, born of unrelated Sri Lankan parents (family 5), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified a homozygous c.616G-A transition (c.616G-A, NM_003937.3) in the KYNU gene resulting in a glu206-to-lys (E206K) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was present in the gnomAD database at an allele frequency of 0.0000199. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the E206K mutation or with wildtype KYNU. The yeast transformed with the mutant KYNU plasmid had a reduced NAD level compared to wildtype.
In a Caucasian patient (family 6) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified compound heterozygous mutations in the KYNU gene: a 3-bp deletion (c.361_363del, NM_003937.3), resulting in deletion of lys121 (Lys121del), and a c.1035T-A transversion, resulting in a ser345-to-arg (S345R; 605197.0010) substitution. The mutation was identified by whole-exome sequencing and the parents were shown to be mutation carriers. The c.361_363del mutation was present in the gnomAD database at an allele frequency of 0.0000177 and the S345R mutation was not present in gnomAD. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the c.361_363del or S345R mutation or with wildtype KYNU. Yeast transformed with S345R mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. Yeast transformed with the c.361_363del or S345R mutant KYNU plasmids had reduced NAD levels compared to wildtype.
For discussion of the c.1035T-A transversion (c.1035T-A, NM_003937.3) in the KYNU gene, resulting in a ser345-to-arg (S345R) substitution, that was found in compound heterozygous state in a patient with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) by Szot et al. (2021), see 605197.0009.
Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M. Isolation and expression of a cDNA clone encoding human kynureninase. Europ. J. Biochem. 239: 460-468, 1996. [PubMed: 8706755] [Full Text: https://doi.org/10.1111/j.1432-1033.1996.0460u.x]
Christensen, M., Duno, M., Lund, A. M., Skovby, F., Christensen, E. Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase. J. Inherit. Metab. Dis. 30: 248-255, 2007. [PubMed: 17334708] [Full Text: https://doi.org/10.1007/s10545-007-0396-2]
Gross, M. B. Personal Communication. Baltimore, Md. 5/30/2014.
Heyes, M. P., Saito, K., Major, E. O., Milstein, S., Markey, S. P., Vickers, J. H. A mechanism of quinolinic acid formation by brain in inflammatory neurological disease: attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain 116: 1425-1450, 1993. [PubMed: 8293279] [Full Text: https://doi.org/10.1093/brain/116.6.1425]
Schule, I., Berger, U., Matysiak, U., Ruzaike, G., Stiller, B., Poul, M., Spiekerkoetter, U., Lausch, E., Grunert, S. C., Schmidts, M. A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-syndrome/VCRL syndrome. Genes (Basel) 12: 879, 2021. [PubMed: 34200361] [Full Text: https://doi.org/10.3390/genes12060879]
Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. NAD deficiency, congenital malformations, and niacin supplementation. New Eng. J. Med. 377: 544-552, 2017. [PubMed: 28792876] [Full Text: https://doi.org/10.1056/NEJMoa1616361]
Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder. Hum. Mutat. 42: 862-876, 2021. [PubMed: 33942433] [Full Text: https://doi.org/10.1002/humu.24211]
Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L. Cloning and recombinant expression of rat and human kynureninase. FEBS Lett. 408: 5-10, 1997. [PubMed: 9180257] [Full Text: https://doi.org/10.1016/s0014-5793(97)00374-8]
Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D. A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population. Circ. Cardiovasc. Genet. 4: 687-694, 2011. [PubMed: 22012986] [Full Text: https://doi.org/10.1161/CIRCGENETICS.110.959064]
Zhu, D. L., Wang, H. Y., Xiong, M. M., He, X., Chu, S. L., Jin, L., Wang, G. L., Yuan, W. T., Zhao, G. S., Boerwinkle, E., Huang, W. Linkage of hypertension to chromosome 2q14-q23 in Chinese families. J. Hypertens. 19: 55-61, 2001. [PubMed: 11204305] [Full Text: https://doi.org/10.1097/00004872-200101000-00008]