HGNC Approved Gene Symbol: NADSYN1
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38) : 11:71,453,203-71,501,816 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Vertebral, cardiac, renal, and limb defects syndrome 3 | 618845 | Autosomal recessive | 3 |
Nicotinamide adenine dinucleotide (NAD) is a coenzyme in metabolic redox reactions, a precursor for several cell signaling molecules, and a substrate for protein posttranslational modifications. NAD synthetase (EC 6.3.5.1) catalyzes the final step in the biosynthesis of NAD from nicotinic acid adenine dinucleotide (NaAD) (summary by Hara et al., 2003).
By searching EST databases for sequences similar to B. subtilis NAD synthetase, followed by PCR of a fetal brain cDNA library and 5-prime RACE of a myeloid leukemia cell cDNA library, Hara et al. (2003) cloned NADSYN1. The deduced 706-amino acid protein contains an N-terminal carbon-nitrogen hydrolase domain, a P-loop ATP-binding site, and a C-terminal NAD synthase domain. Northern blot analysis detected a 3.1-kb transcript in several mouse tissues, with highest expression in small intestine, kidney, liver, and testis, and weaker expression in skeletal muscle, spleen, lung, heart, and brain. Expression was also detected in human glioma and promyelocytic leukemia cell lines.
Stumpf (2020) mapped the NADSYN1 gene to chromosome 11q13.4 based on an alignment of the NADSYN1 sequence (GenBank BC003638) with the genomic sequence (GRCh38).
By biochemical assay of recombinant epitope-tagged NADSYN1 expressed in COS-7 cells, Hara et al. (2003) confirmed that NADSYN1 shows NAD synthetase activity. NADSYN1 utilized both glutamine and ammonia as amide donors. Omission of ATP, Mg(2+), or NaAD resulted in complete loss of NAD synthesis. A mutant NADSYN1 in which cys175, corresponding to the catalytic cysteine in nitrilases (see 604618), was replaced with ser did not utilize glutamine. Migration of the active NADSYN1 species on a nonreducing PAGE gel indicated that NADSYN1 forms a homohexamer.
In 2 sibs with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845), Szot et al. (2020) identified homozygosity for a missense mutation in the NADSYN1 gene (A573T; 608285.0001). Using GeneMatcher, they identified 3 more patients with similar anomalies and homozygous or compound heterozygous mutations in NADSYN1 (see, e.g., 608285.0002-608285.0004).
In 2 sibs (family 1) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845), Szot et al. (2020) identified homozygosity for a c.1717G-A transition (c.1717G-A, NM_018161.5) in the NADSYN1 gene, resulting in an ala573-to-thr (A573T) substitution at a highly conserved residue within the P2 loop of the NAD synthetase domain. Their unaffected parents were heterozygous for the mutation. Using GeneMatcher, the authors identified a similarly affected male infant (family 2) who was compound heterozygous for the A573T mutation and a 1-bp deletion (c.1819del; 608285.0002), causing a frameshift predicted to result in a premature termination codon (Val607TrpfsTer30). His unaffected parents were each heterozygous for 1 of the mutations. The A573T and c.1819del mutations were both present at low minor allele frequency in the gnomAD database (7.40 x 10(-4) and 7.07 x 10(-6), respectively). In yeast complementation assays, the A573T mutant showed an 86% decrease in total cellular NAD compared to wildtype NADSYN1. Enzymatic assays in transfected COS7 cells showed an approximately 342-fold reduction in NAD synthetase-specific activity with the mutant compared to wildtype protein.
For discussion of the 1-bp deletion (c.1819del, NM_018161.5) in the NADSYN1 gene, causing a frameshift predicted to result in a premature termination codon (Val607TrpfsTer30), that was found in compound heterozygous state in a male infant (family 2) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845) by Szot et al. (2020) through GeneMatcher, see 608285.0001.
Using GeneMatcher, Szot et al. (2020) identified a male infant (family 4) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845) who was compound heterozygous for a c.735T-A transversion (c.735T-A, NM_018161.5) in the NADSYN1 gene, resulting in a cys245-to-ter (C245X) substitution, and a c.1839C-G transversion, resulting in a tyr613-to-ter (Y613X) substitution. His unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in the gnomAD database.
For discussion of the c.1839C-G transversion (c.1839C-G, NM_018161.5) in the NADSYN1 gene, resulting in a tyr613-to-ter (Y613X) substitution, that was reported in compound heterozygous state in a patient (family 4) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845) by Szot et al. (2020), see 608285.0003.
Hara, N., Yamada, K., Terashima, M., Osago, H., Shimoyama, M., Tsuchiya, M. Molecular identification of human glutamine- and ammonia-dependent NAD synthetases: carbon-nitrogen hydrolase domain confers glutamine dependency. J. Biol. Chem. 278: 10914-10921, 2003. Note: Erratum: J. Biol. Chem. 278: 41572 only, 2003. [PubMed: 12547821] [Full Text: https://doi.org/10.1074/jbc.M209203200]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/10/2020.
Szot, J. O., Campagnolo, C., Cao, Y., Iyer, K. B., Cuny, H., Drysdale, T., Flores-Daboub, J. A., Bi, W., Westerfield, L., Liu, P., Leung, T. N., Choy, K. W., Chapman, G., Xiao, R., Siu, V. M., Dunwoodie, S. L. Bi-allelic mutations in NADSYN1 cause multiple organ defects and expand the genotypic spectrum of congenital NAD deficiency disorders. Am. J. Hum. Genet. 106: 129-136, 2020. [PubMed: 31883644] [Full Text: https://doi.org/10.1016/j.ajhg.2019.12.006]