Alternative titles; symbols
HGNC Approved Gene Symbol: NMNAT1
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38) : 1:9,942,923-9,996,892 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | Leber congenital amaurosis 9 | 608553 | Autosomal recessive | 3 |
| Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis | 619260 | Autosomal recessive | 3 |
The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca(2+) signaling pathways. NMNAT (EC 2.7.7.1) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD (Zhang et al., 2003).
By searching an EST database for sequences similar to peptide fragments of NMNAT1 purified from placenta, followed by PCR of a placenta cDNA library, Emanuelli et al. (2001) cloned NMNAT1. The deduced 279-amino acid protein has a calculated molecular mass of 31.9 kD. It contains a conserved N-terminal adenylyltransferase motif, an N-terminal N-glycosylation site, and several potential transmembrane regions. Northern blot analysis detected 3.1- and 4.1-kb transcripts expressed at variable levels in all tissues examined. The 3.1-kb transcript was more abundant, and expression was highest in skeletal muscle, heart, liver, and kidney; thymus and spleen showed a weak signal. Expression was reduced in all tumor cell lines examined except in a lymphoma cell line and a chronic myelogenous leukemia cell line. Purified recombinant NMNAT1 migrated with an apparent molecular mass of 33 kD by SDS-PAGE. Gel filtration analysis detected active recombinant enzyme at an apparent molecular mass of 139 kD, suggesting that NMNAT1 forms a homotetramer.
Schweiger et al. (2001) cloned NMNAT1 from a lymphoblastoid cell cDNA library. The deduced protein contains an N-terminal nuclear localization signal. Immunofluorescence microscopy localized endogenous NMNAT1 to the nucleus in human fibroblasts and in a hepatoma cell line.
Fernando et al. (2002) determined that the human and mouse NMNAT1 proteins share 78.4% amino acid identity. Northern blot analysis detected an abundant 3.1-kb transcript and a less abundant 4.1-kb transcript in skeletal muscle, heart, and all brain regions examined.
Using immunofluorescence analysis, Berger et al. (2005) showed that fluorescence-tagged NMNAT1 localized exclusively within nuclei of transfected HeLa and HEK293 cells, similar to the endogenous protein.
In addition to canonical isoform 1 of NMNAT1 and alternative isoform 2, Bedoni et al. (2020) identified a third isoform present in healthy human tissues. Levels of expression were highest for isoform 1 in all tissues tested, followed by isoform 2; novel isoform 3 presented lower levels of expression, but was always detected.
Using an Nmnat1-lacZ fusion protein lacking the nuclear localization signal, Sasaki et al. (2020) showed that Nmnat1 was ubiquitously expressed in mouse retina.
Fernando et al. (2002) determined that the NMNAT1 gene contains 4 exons.
By FISH, Emanuelli et al. (2001) mapped the NMNAT1 gene to chromosome 1p35-p32. Southern blot analysis indicated that NMNAT1 is a single-copy gene.
Using FISH, Fernando et al. (2002) mapped the NMNAT1 gene to chromosome 1p36.2 in a region that shows homology of synteny to distal mouse chromosome 4. FISH and genomic sequence analyses identified several NMNAT1 homologs on chromosomes 3, 4, 14, and 15.
Zhou et al. (2002) solved the crystal structures of NMNAT1 in complex with NAD, deamido-NAD, and a nonhydrolyzable analog of the anticancer drug tiazofurin. The structures suggested a mechanism for the broad substrate specificity of the enzyme toward both NMN and NaMN and for adenylation of tiazofurin nucleotide. The crystal structure also showed that NMNAT1 forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role in interacting with nuclear transporting proteins. Analytic ultracentrifugation results were consistent with the formation of a hexamer in solution under certain conditions.
Emanuelli et al. (2001) confirmed that recombinant NMNAT1 exhibited adenylyltransferase activity, converting NMN to NAD in the presence of ATP. When deamido-NMN was used as the substrate, the rate of reaction was comparable to that for NMN, but the K(m) was higher, suggesting that the amido pathway is predominant. NMNAT1 had an absolute requirement for divalent cations, with optimum activity with 12 mM Mg(2+), and activity was depressed by several heavy metal ions. NMNAT1 also showed a broad pH optimum, ranging from pH 6.0 to 8.0, similar to NMNAT purified from other species.
Schweiger et al. (2001) demonstrated that NMNAT1 inhibited recombinant human poly(ADP-ribose) polymerase-1 (ADPRT; 173870) by about 35%, and it completely prevented the formation of branched ADP-ribose polymers. NMNAT1 was not itself an acceptor protein for ADP-ribosylation. Incubation with nuclear extracts resulted in phosphorylation of recombinant NMNAT1.
In Wallerian degeneration slow (wld-s) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wld-s) composed of the ubiquitin assembly protein Ufd2a (603753) and Nmnat1. Araki et al. (2004) demonstrated that increased Nmnat activity is responsible for the axon-sparing activity of the Wld-s protein. Furthermore, they demonstrated that Sirt1 (604479) is the downstream effector of increased Nmnat activity that leads to axonal protection. Araki et al. (2004) concluded that novel therapeutic strategies directed at increasing the supply of NAD and/or SIR2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration.
Using purified recombinant proteins, Berger et al. (2005) compared the enzymatic properties of NMNAT1, NMNAT2 (608701), and NMNAT3 (608702). NMNAT3 exhibited a high tolerance for substrate modifications. In contrast with the preferred NAD+ synthesis by NMNAT1, NMNAT2 and NMNAT3 could also form NADH directly from the reduced nicotinamide mononucleotide. A variety of physiologic intermediates had only minor influence on NMNAT catalytic activity. However, gallotannin was a potent inhibitor of NMNAT catalytic activity.
Studies in Drosophila (see ANIMAL MODEL) have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase against activity-induced neurodegeneration and injury-induced axonal degeneration (Zhai et al., 2006, MacDonald et al., 2006). Zhai et al. (2008) showed that NMNAT overexpression can also protect against ataxin (601556)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein-70 (HSP70; 140550). NMNAT displayed chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of polyglutamine-expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Zhai et al. (2008) concluded that their results implicated NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection.
Leber Congenital Amaurosis 9
In 8 families with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified homozygosity or compound heterozygosity for missense mutations in the NMNAT1 gene (see, e.g., 608700.0001-608700.0007) that segregated with disease in each family.
In 11 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for missense and/or nonsense mutations in the NMNAT1 gene (see, e.g., 608700.0002-608700.0004 and 608700.0006). The most common variant, E257K (rs150726175; 608700.0002), was present as 1 of 2 variant alleles in all 11 probands and was estimated to have an allele frequency of 0.001.
In affected individuals from 14 families with severe LCA, Falk et al. (2012) identified homozygosity or compound heterozygosity for missense and/or frameshift mutations in the NMNAT1 gene (see, e.g., 608700.0009), including 6 patients who carried the E257K mutation on 1 allele.
In 22 of 261 LCA probands without mutations in known LCA genes, Perrault et al. (2012) identified homozygosity (608700.0006) or compound heterozygosity for mutations in the NMNAT1 gene (see, e.g., 608700.0002 and 608700.0005). In 7 probands, only a single heterozygous NMNAT1 mutation was found, but because they presented an identical phenotype to that of patients in whom 2 mutations were identified it was likely that they harbored a second undetected NMNAT1 mutant allele. The most common mutation detected was the E257K variant, which was present on 1 allele in 23 of the 29 index cases with mutation in NMNAT1.
In an Arab sister and brother with early-onset retinal dystrophy with central nummular macular atrophy, Khan et al. (2018) identified homozygosity for a missense mutation in the NMNAT1 gene (N167S; 608700.0012) that segregated with disease in the family and was not found in public variant databases.
In a 26-year-old Indian woman with early-onset retinal dystrophy and coloboma-like macular atrophy, Nash et al. (2018) identified homozygosity for a missense mutation in the NMNAT1 gene (E91K; 608700.0013). A similarly affected 14-year-old Caucasian girl was found to be compound heterozygous for the common E257K variant and another missense mutation in the NMNAT1 gene (N18S; 608700.0014).
From a Spanish cohort of 76 patients with LCA or early-onset retinal dystrophy, Bedoni et al. (2020) identified a 6-year-old boy with LCA who was compound heterozygous for the common E257K variant and a 7.4-bp duplication within the NMNAT1 gene (608700.0010).
In an Egyptian brother and sister with early-onset progressive retinal dysfunction with foveal hypoplasia, Bedoukian et al. (2020) identified compound heterozygous mutations in the NMNAT1 gene: the E257K variant and another missense mutation (V82L; 608700.0015). The authors concluded that NMNAT1 mutations cause a consistent phenotype characterized by early-onset progressive retina-wide dysfunction, affecting cones more than rods, with predominantly central abnormalities ranging from hypoplasia to atrophy of the fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance.
In a sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene, noting that these cases extended the phenotypic spectrum associated with the NMNAT1 gene.
Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis
In an Italian brother and sister and an unrelated Italian boy with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication within the NMNAT1 gene (608700.0010).
In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation in the NMNAT1 gene (608700.0011).
Zhai et al. (2006) found that knockdown of Nmnat in Drosophila resulted in retinal neurodegeneration that was exacerbated by neural activity. Neurodegeneration was independent of apoptosis. Overexpression of an inactive Nmnat mutant protected mutant retinas from activity-induced neurodegeneration, suggesting a dual role for Nmnat in NAD synthesis and in maintaining neuronal integrity.
Studying glaucoma-prone mice (the DBA/2J strain), Williams et al. (2017) showed that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults, including increased intraocular pressure. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD(+)-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. Williams et al. (2017) concluded that their results supported therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations.
Sasaki et al. (2020) noted that knockout of Nmnat1 in mice is embryonic lethal. They found that conditional knockout of Nmnat1 in 2-month-old mice induced loss of photoreceptor cells and inhibited retinal function, leading to severe retinal degeneration. Photoreceptor-specific depletion of Nmnat1 also resulted in retinal degeneration, which could be partially rescued by transgenic expression of Nmnat1. Further analysis demonstrated that loss of Nmnat1 in photoreceptors activated Sarm1 (607732), and that Sarm1 was required for subsequent photoreceptor degeneration and loss of visual function. Consequently, depletion of Sarm1 rescued retinal degeneration in Nmnat1-deficient retina.
In affected members of a large consanguineous Pakistani family with Leber congenital amaurosis (LCA9; 608553), originally reported by Keen et al. (2003), Koenekoop et al. (2012) identified homozygosity for an 838T-C transition in the NMNAT1 gene, resulting in a ter280-to-gln (X280Q) substitution that was predicted to elongate the protein.
In 5 probands with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified a 769G-A transition in exon 5 of the NMNAT1 gene, resulting in a glu257-to-lys (E257K) substitution at a conserved residue in a protein-interaction domain interface, predicted to interfere with hexamer formation. The mutation was found in homozygosity in 1 proband, and was present in compound heterozygosity with another missense mutation in the NMNAT1 gene in the other 4 probands (see, e.g., 608700.0003-608700.0005). All mutations segregated with disease in each family and were not found in 200 controls. In red blood cells (RBCs) from the patient homozygous for E257K there was a significantly lower concentration of NAD compared with that in RBCs from his heterozygous mother, suggesting reduced enzymatic function of the mutant protein. Immunohistochemical studies in transfected HeLa cells demonstrated that whereas wildtype NMNAT1 showed strong nuclear staining, the E257K mutant stained strongly outside of the cell nucleus in the cytoplasm; in addition, the mutant protein was positive for ubiquitin staining, indicating that the mutation likely affects protein folding. In vitro assay showed significantly reduced enzymatic activity with the E257K mutant protein compared to wildtype.
In 11 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or nonsense mutation in the NMNAT1 gene (see, e.g., N273D, 608700.0003; V151F, 608700.0004; and W169X, 608700.0006). Chiang et al. (2012) stated that the allele frequency of E257K (rs150726175) was estimated to be 0.001, whereas the remainder of the variants had not been reported in any public database.
In 6 probands with LCA, Falk et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or frameshift mutation in the NMNAT1 gene.
Perrault et al. (2012) identified the E257K variant on 1 allele in 23 of 29 probands with LCA in whom mutation in NMNAT1 was detected.
In a 6-year-old Spanish boy with LCA, Bedoni et al. (2020) identified compound heterozygosity for the E257K variant and a 7.4-kb duplication within the NMNAT1 gene (608700.0010).
In a 14-year-old Caucasian girl (case 2) with early-onset retinal dystrophy and coloboma-like macular atrophy, Nash et al. (2018) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.53A-G transition, resulting in an asn18-to-ser (N18S; 608700.0014) substitution. The N18S variant was present in 5 of 276,912 alleles in the gnomAD database (minor allele frequency, 0.000018). The authors noted that ERG findings in this patient showed reduced photopic and scotopic responses, consistent with cone-rod dystrophy.
In an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia, consistent with cone-rod dystrophy, Bedoukian et al. (2020) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.245T-C transition, resulting in a val82-to-ala (V82A; 608700.0015) substitution. Their unaffected parents were each heterozygous for one of the mutations.
In a sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene. Their unaffected parents were each heterozygous for one of the mutations.
In a 56-year-old French Canadian woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for an 817A-G transition in exon 5 of the NMNAT1 gene, resulting in an asn273-to-asp (N273D) substitution at a conserved residue, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype.
In an 8-year-old Canadian boy of western European ancestry who had severe LCA, Chiang et al. (2012) identified compound heterozygosity for the N273D and E257K mutations in the NMNAT1 gene. The E257K and N273D mutations were inherited from his unaffected mother and father, respectively, and a third mutation was detected on the paternal allele as well: a 457C-G transversion in the NMNAT1 gene, resulting in a leu153-to-val (L153V; 608700.0008) substitution near the site of ligand binding, predicted to disturb local interactions and affect enzymatic activity. At 7 years of age, ERG showed primarily cone dysfunction rather than profound loss of all responses, and the patient's diagnosis was revised from 'variant LCA' to 'cone-rod dystrophy.'
In a European female with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 451G-A transition in exon 5 of the NMNAT1 gene, resulting in a val151-to-phe (V151F) substitution at a conserved residue in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype.
In a 26-year-old Canadian man of Greek ancestry with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the V151F and E257K mutations in the NMNAT1 gene. At 6 months of age, the patient was diagnosed with retinitis pigmentosa (see 268000), but the diagnosis was later changed to LCA. Major vision loss occurred around 18 years of age, with colors and shapes still seen at age 20, at which time he began using a guide dog. Colors and shapes were lost at 22 years and 24 years of age, respectively, and by 26 years of age, the patient could only distinguish between light and dark. Eye examination showed wandering eye movements, macular atrophic lesions, attenuated vessels, and bone spicule pigmentation.
In a 13-year-old French Canadian boy with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 619C-T transition in exon 5 of the NMNAT1 gene, resulting in an arg207-to-trp (R207W) substitution in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype.
In 7 unrelated probands with LCA, Perrault et al. (2012) identified compound heterozygosity for the R207W and E257K mutations in the NMNAT1 gene.
In a 33-year-old Irish woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 507G-A transition in exon 5 of the NMNAT1 gene, resulting in a trp169-to-ter (W169X) substitution, and a 710G-T transversion in exon 5, resulting in an arg237-to-leu (R237L; 608700.0007) substitution, both at conserved residues in the adenylyltransferase domain. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 200 controls.
In 4 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the W169X and E257K (608700.0002) mutations in the NMNAT1 gene. Chiang et al. (2012) noted that these patients who carried the nonsense mutation W169X in combination with E257K were all blind at birth and had only varying degrees of light perception still present, whereas 5 patients who carried various missense mutations in combination with E257K had vision that decreased within a few years after birth.
In a 16-year-old girl with LCA who was born of consanguineous Algerian parents, Perrault et al. (2012) identified homozygosity for the W169X mutation in the NMNAT1 gene. Her unaffected parents and sister were heterozygous for the mutation, which was not found in 200 controls. The patient had high hyperopia, night blindness, visual acuity at the level of counting fingers since 4 years of age, and macular alteration.
For discussion of the arg273-to-leu (R273L) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; 608553) by Koenekoop et al. (2012), see 608700.0006.
For discussion of the leu153-to-val (L153V) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; 608553) by Chiang et al. (2012), see 608700.0003.
In 3 sibs and 2 cousins from a consanguineous Pakistani pedigree with Leber congenital amaurosis (LCA9; 608553), Falk et al. (2012) identified homozygosity for a 25G-A transition in exon 2 of the NMNAT1 gene, resulting in a val9-to-met (V9M) substitution at a highly conserved residue. The mutation segregated with disease in the pedigree and was not found in 501 controls or in any public databases. Only 1 of the affected individuals had isolated LCA; 3 of the other LCA patients also had congenital deafness, and in those patients as well as in 2 other family members with congenital deafness, homozygosity for a nonsense mutation in the GJB2 gene (W24X; 121011.0003) known to cause deafness (see DFNB1A, 220290) was identified. Additional features in 4 of the LCA patients included global developmental delay and autism; Falk et al. (2012) stated that those presentations likely had a separate genetic etiology from that of LCA and deafness in this pedigree.
Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis
In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy (P3; 947-13) with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication (c.299+526_Ter968dup, NM_022787.3) involving exons 4 and 5 of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The unaffected parents were heterozygous for the duplication, which was found to be embedded in a common haplotype, indicating that it represented a founder mutation. The authors suggested that the Alu elements flanking the duplicated fragment, AluSx and AluSx3, might have mediated a tandem duplication event by nonallelic homologous recombination. Analysis of patient fibroblasts showed a 4-fold downregulation of NMNAT1, and RT-PCR revealed a heterogeneous population of aberrant mRNA isoforms, variably showing partial retention of intron 3, duplication of exon 4, and duplication of exon 4 and part of exon 5, as well as some wildtype transcript.
In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation (c.439+5G-T) in intron 4 of the NMNAT1 gene. Her unaffected father, who was of Bulgarian origin, was heterozygous for the splicing mutation; DNA was unavailable from her biological mother, as the child was born from an ovum donation procedure. Total NMNAT1 expression in the proband was reduced by approximately 25% compared to controls. Expression assays indicated that the duplication decreases the levels of the known NMNAT1 canonical isoform 1 and alternative isoform 2, whereas the splicing mutation alters the relative expression of NMNAT1 isoforms.
Leber Congenital Amaurosis 9
Bedoni et al. (2020) performed PCR screening in a Spanish cohort of 76 patients with Leber congenital amaurosis (LCA) or early-onset retinal dystrophy and identified a 6-year-old boy with LCA (LCA9; 608553) who was compound heterozygous for the common E257K variant in the NMNAT1 gene (608700.0002) and the 7.4-bp duplication. Haplotype analysis in the Spanish boy revealed rare heterozygous SNP genotypes in proximity to the duplication which were shared with the Italian patients, indicating a common and likely remote ancestral genetic event.
For discussion of the splicing mutation (c.439+5G-T, NM_022787.3) in intron 4 of the NMNAT1 gene that was found in compound heterozygous state in a 2-year-old Spanish girl with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260) by Abad-Morales et al. (2021), see 608700.0010.
In a sister and brother from a consanguineous Arab family who had retinal degeneration within the first few years of life, accompanied by nummular macular atrophy (LCA9; 608700), Khan et al. (2018) identified homozygosity for a c.500A-G transition in the NMNAT1 gene, resulting in an asn167-to-ser (N167S) substitution at a highly conserved residue within the NMNAT domain. The mutation segregated with disease in the family and was not found in the ExAC or gnomAD databases. Patient samples were not available for functional analysis of the mutation. Electroretinography, performed in the sister, showed reduced responses more of cones than rods, consistent with a cone-rod dystrophy.
In a 26-year-old Indian woman (case 1) with early-onset retinal dystrophy and coloboma-like macular atrophy (LCA9; 608700), Nash et al. (2018) identified homozygosity for a c.271G-A transition (c.271G-A, NM_022787.3) in the NMNAT1 gene, resulting in a glu91-to-lys (E91K) substitution at a conserved residue. The variant was present in 1 of 245,660 alleles in the gnomAD database (minor allele frequency, 0.000004). The authors considered the loss of central vision and ERG findings in this patient to be consistent with cone dystrophy.
For discussion of the c.53A-G transition in the NMNAT1 gene, resulting in an asn18-to-ser (N18S) substitution, that was found in compound heterozygous state in patients with early-onset retinal dystrophy and severe macular atrophy (LCA9; 608553) by Nash et al. (2018) and Kumaran et al. (2021), see 608700.0002.
For discussion of the c.245T-C transition in the NMNAT1 gene, resulting in a val82-to-ala (V83A) substitution, that was found in compound heterozygous state in an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia (LCA9; 608553) by Bedoukian et al. (2020), see 608700.0002.
Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform. Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article. [PubMed: 33668384] [Full Text: https://doi.org/10.3390/ijms22052262]
Araki, T., Sasaki, Y., Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305: 1010-1013, 2004. [PubMed: 15310905] [Full Text: https://doi.org/10.1126/science.1098014]
Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs. Hum. Molec. Genet. 29: 2250-2260, 2020. [PubMed: 32533184] [Full Text: https://doi.org/10.1093/hmg/ddaa112]
Bedoukian, E. C., Zhu, X., Serrano, L. E., Scoles, D., Aleman, T. S. NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment. Retin. Cases Brief Rep. 4Mar, 2020. [PubMed: 32150116] [Full Text: https://doi.org/10.1097/ICB.0000000000000992]
Berger, F., Lau, C., Dahlmann, M., Ziegler, M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem. 280: 36334-36341, 2005. [PubMed: 16118205] [Full Text: https://doi.org/10.1074/jbc.M508660200]
Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nature Genet. 44: 972-974, 2012. [PubMed: 22842231] [Full Text: https://doi.org/10.1038/ng.2370]
Emanuelli, M., Carnevali, F., Saccucci, F., Pierella, F., Amici, A., Raffaelli, N., Magni, G. Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase. J. Biol. Chem. 276: 406-412, 2001. [PubMed: 11027696] [Full Text: https://doi.org/10.1074/jbc.M008700200]
Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others. NMNAT1 mutations cause Leber congenital amaurosis. Nature Genet. 44: 1040-1045, 2012. [PubMed: 22842227] [Full Text: https://doi.org/10.1038/ng.2361]
Fernando, F. S., Conforti, L., Tosi, S., Smith, A. D., Coleman, M. P. Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse. Gene 284: 23-29, 2002. [PubMed: 11891043] [Full Text: https://doi.org/10.1016/s0378-1119(02)00394-3]
Keen, T. J., Mohamed, M. D., McKibbin, M., Rashid, Y., Jafri, H., Maumenee, I. H., Inglehearn, C. F. Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36. Europ. J. Hum. Genet. 11: 420-423, 2003. [PubMed: 12734549] [Full Text: https://doi.org/10.1038/sj.ejhg.5200981]
Khan, A. O., Budde, B. S., Nurnberg, P., Kawalia, A., Lenzner, S., Bolz, H. J. Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype. Clin. Genet. 93: 149-154, 2018. [PubMed: 28369829] [Full Text: https://doi.org/10.1111/cge.13022]
Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nature Genet. 44: 1035-1039, 2012. [PubMed: 22842230] [Full Text: https://doi.org/10.1038/ng.2356]
Kumaran, N., Robson, A. G., Michaelides, M. A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum. Retin. Cases Brief Rep. 15: 139-144, 2021. [PubMed: 30004997] [Full Text: https://doi.org/10.1097/ICB.0000000000000754]
MacDonald, J. M., Beach, M. G., Porpiglia, E., Sheehan, A. E., Watts, R. J., Freeman, M. R. The Drosophila cell corpse engulfment receptor draper mediates glial clearance of severed axons. Neuron 50: 869-881, 2006. [PubMed: 16772169] [Full Text: https://doi.org/10.1016/j.neuron.2006.04.028]
Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V. NMNAT1 variants cause cone and cone-rod dystrophy. Europ. J. Hum. Genet. 26: 428-433, 2018. [PubMed: 29184169] [Full Text: https://doi.org/10.1038/s41431-017-0029-7]
Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others. Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. Nature Genet. 44: 975-977, 2012. [PubMed: 22842229] [Full Text: https://doi.org/10.1038/ng.2357]
Sasaki, Y., Kakita, H., Kubota, S., Sene, A., Lee, T. J., Ban, N., Dong, Z., Lin, J. B., Boye, S. L., DiAntonio, A., Boye, S. E., Apte, R. S., Milbrandt, J. SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration. eLife 9: e62027, 2020. [PubMed: 33107823] [Full Text: https://doi.org/10.7554/eLife.62027]
Schweiger, M., Hennig, K., Lerner, F., Niere, M., Hirsch-Kauffmann, M., Specht, T., Weise, C., Oei, S. L., Ziegler, M. Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis. FEBS Lett. 492: 95-100, 2001. Note: Erratum: FEBS Lett. 496: 68 only, 2001. [PubMed: 11248244] [Full Text: https://doi.org/10.1016/s0014-5793(01)02180-9]
Williams, P. A., Harder, J. M., Foxworth, N. E., Cichran, K. E., Philip, V. M., Porciatti, V., Smithies, O., John, S. W. M. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355: 756-760, 2017. [PubMed: 28209901] [Full Text: https://doi.org/10.1126/science.aal0092]
Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., Bellen, H. J. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biol. 4: e416, 2006. Note: Electronic Article. [PubMed: 17132048] [Full Text: https://doi.org/10.1371/journal.pbio.0040416]
Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., Bellen, H. J. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452: 887-891, 2008. [PubMed: 18344983] [Full Text: https://doi.org/10.1038/nature06721]
Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., Zhang, H. Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis. J. Biol. Chem. 278: 13503-13511, 2003. [PubMed: 12574164] [Full Text: https://doi.org/10.1074/jbc.M300073200]
Zhou, T., Kurnasov, O., Tomchick, D. R., Binns, D. D., Grishin, N. V., Marquez, V. E., Osterman, A. L., Zhang, H. Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase: basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin. J. Biol. Chem. 277: 13148-13154, 2002. [PubMed: 11788603] [Full Text: https://doi.org/10.1074/jbc.M111469200]