current
NMNAT1:c.769G>A (p.Glu257Lys) AND Leber congenital amaurosis 9
current
classified by multiple submitters
Pathogenic
Pathogenic;pathogenic
germline
human
not provided
curation
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.
22842230
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.
22842231
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.
22842227
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.
22842229
not provided
human
not provided
assert pathogenicity
curation
not provided
NMNAT1:c.769G>A (p.Glu257Lys)
NMNAT1, GLU257LYS (rs150726175)
0.001076426265
0.0005
missense
NM_022787.3:c.769G>A
NG_032954.1:g.44203G>A
NC_000001.10:g.10042688G>A
NP_073624.2:p.Glu257Lys
E257K
GLU257LYS
1p36.2
nicotinamide nucleotide adenylyltransferase 1
NMNAT1
Leber congenital amaurosis 9
Leber Congenital Amaurosis
LCA9
Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal.
Neonatal/infancy
1-9 / 100 000
20301475
current
Pathogenic
germline
human
not provided
curation
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.
22842230
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.
22842231
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.
22842227
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.
22842229
NMNAT1, GLU257LYS (rs150726175)
GLU257LYS (rs150726175)
NMNAT1
LEBER CONGENITAL AMAUROSIS 9
current
pathologic
not provided
human
not provided
Assert pathogenicity
curation
not provided
NM_022787.3:c.769G>A
Leber Congenital Amaurosis