Alternative titles; symbols
HGNC Approved Gene Symbol: NAXE
SNOMEDCT: 1251447008;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38) : 1:156,591,776-156,594,299 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy | 617186 | Autosomal recessive | 3 |
The NAXE gene encodes an epimerase that catalyzes the conversion of R-NAD(P)HX to S-NAD(P)HX, which are toxic cellular metabolites, so that S-NAD(P)HX can be reconverted to S-NAD(P)H by the dehydratase NAXD (615910). This pathway is involved in the protection of the cell from reactive oxygen species (summary by Kremer et al., 2016).
APOA1BP interacts with apolipoprotein A-I (APOA1; 107680) and is involved in cholesterol transfer. It is also predicted to function as an epimerase in the repair of (R)-epimers of hydrated NADH and NADPH (summary by Marbaix et al., 2014).
Using the mature APOA1 protein (107680) as bait in a yeast 2-hybrid screen of a liver cDNA library, Ritter et al. (2002) cloned full-length APOA1BP, which they designated AIBP. The deduced 288-amino acid protein has a calculated molecular mass of 31.6 kD. APOA1BP contains an N-terminal signal peptide for translocation into the endoplasmic reticulum, a putative signal sequence cleavage site, and several putative phosphorylation and O-glycosylation sites. The processed mature protein has a calculated molecular mass of 29.1 kD. Human APOA1BP shares 88.2 to 89.5% amino acid identity with mouse, bovine, and porcine Apoa1bp. RNA dot blot analysis revealed abundant APOA1BP expression in all adult and fetal tissues investigated. Highest expression was in kidney, apex of heart, liver, thyroid gland, adrenal gland, and testis. APOA1BP was also expressed in all cell lines examined. Western blot analysis detected a 29-kD APOA1BP protein in hepatoma cell lysates and, to a lesser extent, in the culture medium. APOA1BP was also detected in cerebrospinal fluid (CSF) and urine of healthy volunteers, but not in normal serum samples. One of 3 patients with septic syndromes showed detectable serum APOA1BP. In sepsis serum and normal CSF, APOA1BP migrated as a complex with an apparent molecular mass of about 80 kD; no 29-kD monomeric APOA1BP was detected.
Marbaix et al. (2014) identified 2 highly conserved methionines separated by approximately 50 residues at the N terminus of mouse and human AIBP. EST database analysis revealed that both were used as initiation methionines. The longer protein was predicted to be targeted to mitochondria, and the shorter protein was predicted to be cytosolic. The long and short isoforms of mouse Aibp were expressed in mitochondria and cytosol, respectively, following transfection of Chinese hamster ovary cells.
Ritter et al. (2002) confirmed direct binding between APOA1 and APOA1BP by in vitro protein binding assays and copurification of the 2 proteins from hepatoma cell lysates. APOA1BP also bound APOA2 (107670) and high density lipoprotein (HDL). Stimulation of a human proximal tubular cell line with APOA1 and HDL resulted in secretion of APOA1BP in a dose-dependent manner. Secretion of APOA1BP was not increased in colon carcinoma or hepatoma cell lines following stimulation. Individuals with impaired renal function, as well as mice with resorption deficiency due to a megalin (600073) mutation, showed increased excretion of APOA1BP, indicating that APOA1BP is a reabsorbed protein.
Fang et al. (2013) showed that AIBP accelerates cholesterol efflux from endothelial cells to HDL and thereby regulates angiogenesis. AIBP- and HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 (191306) dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Notably, Aibp, a zebrafish homolog of human AIBP, regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell-autonomous regulator of angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, whereas forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1 (600046) Abcg1 (603076)-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1 Abcg1-deficient embryos. Fang et al. (2013) concluded that their findings demonstrated that secreted AIBP positively regulates cholesterol efflux from endothelial cells and that effective cholesterol efflux is critical for proper angiogenesis.
Ritter et al. (2002) determined that the APOA1BP gene contains 6 exons and spans 2.5 kb. The putative promoter region contains no TATA box, but it has a GC-rich region proximal to the transcription start site. APOA1BP has several putative transcription factor binding sites common to genes involved in lipid metabolism.
By genomic sequence analysis, Ritter et al. (2002) mapped the APOA1BP gene to chromosome 1q21.2-q22.
In 5 sibs, born of consanguineous parents of Arab Muslim origin, with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Spiegel et al. (2016) identified a homozygous missense mutation in the NAXE gene (A94D; 608862.0001). The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed. Given the role of NAXE in the repair of hydrated NAD and NADP cofactors, Spiegel et al. (2016) hypothesized that compromised NAXE function may result in abnormal accumulation of toxic metabolites, especially during illness or stress, similar to that observed in patients with vanishing white matter due to mutations in EIF2B genes (see, e.g., EIF2B1, 606686).
In 5 patients from 4 unrelated families with PEBEL, Kremer et al. (2016) identified homozygous or compound heterozygous mutations in the NAXE gene (608862.0002-608862.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from 2 unrelated patients showed significantly increased levels of the toxic metabolite cyclic-NADHX, as well as increased levels of R-NADHX and S-NADHX, compared to controls. There was also a gradual increase in these toxic metabolites after NAXE cells were exposed to heat stress. The findings confirmed deficiency of the mitochondrial NAD(P)HX repair system, resulting in the accumulation of toxic metabolites that are known to inhibit various cellular NADH dehydrogenases.
In 5 sibs, born of consanguineous parents of Arab Muslim origin, with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Spiegel et al. (2016) identified a homozygous c.281C-A transversion (c.281C-A, NM_144772) in the NAXE gene, resulting in an ala94-to-asp (A94D) substitution at a highly conserved residue. The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in about 61,000 control exomes. Functional studies of the variant were not performed. Given the role of NAXE in the repair of hydrated NAD and NADP cofactors, Spiegel et al. (2016) hypothesized that compromised NAXE function may result in abnormal accumulation of toxic metabolites especially during illness or stress, similar to that observed in patients with vanishing white matter due to mutations in EIF2B genes (see, e.g., EIF2B1, 606686).
In a male infant, born of consanguineous parents of Gambian descent (family 1), with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Kremer et al. (2016) identified a homozygous c.177C-A transversion in exon 1 of the NAXE gene, resulting in a tyr59-to-ter (Y59X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases, including ExAC (March 2015). Western blot analysis of patient fibroblasts showed complete loss of the NAXE protein. The patient's sister was similarly affected, although DNA was not available.
In a female infant from Croatia (family 2) with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Kremer et al. (2016) identified compound heterozygous mutations in the NAXE gene: a c.196C-T transition in exon 2, resulting in a gln66-to-ter (Q66X) substitution, and a G-to-A transition in intron 4 (c.516+1G-A; 608862.0004), predicted to result in a splice site alteration. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.196C-T variant was found 4 times and the splice site variant once in the ExAC database (March 2015). Western blot analysis of patient fibroblasts showed complete loss of the NAXE protein.
For discussion of the G-to-A transition in intron 4 of the NAXE gene (c.516+1G-A), resulting in a splice site alteration, that was found in compound heterozygous state in an infant with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186) by Kremer et al. (2016), see 608862.0003.
In a male infant, born of unrelated German parents (family 3), with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Kremer et al. (2016) identified a homozygous c.804_807del/insA mutation in exon 6 of the NAXE gene, resulting in an in-frame deletion of conserved residue Lys270 (Lys270del). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases, including ExAC (March 2015). Western blot analysis of patient fibroblasts showed reduced levels of the NAXE protein.
In 2 male infant sibs of Polish descent (family 4) with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186), Kremer et al. (2016) identified compound heterozygous mutations in the NAXE gene: a 1-bp deletion (c.743delC) in exon 6, resulting in a frameshift and premature termination (Ala248GlufsTer26), and a c.653A-T transversion in exon 5, resulting in an asp218-to-val (D218V; 608862.0007) substitution at a highly conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in public databases, including ExAC (March 2015). Functional studies of the variants and studies of patient cells were not performed. These sibs (proband 12) were also reported by Pronicka et al. (2016).
For discussion of the c.653A-T transversion in exon 5 of the NAXE gene, resulting in an asp218-to-val (D218V) substitution, that was found in compound heterozygous state in infants with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL; 617186) by Kremer et al. (2016), see 608862.0006.
Fang, L., Choi, S.-H., Baek, J. S., Liu, C., Almazan, F., Ulrich, F., Wiesner, P., Taleb, A., Deer, E., Pattison, J., Torres-Vazquez, J., Li, A. C., Miller, Y. I. Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 498: 118-122, 2013. [PubMed: 23719382] [Full Text: https://doi.org/10.1038/nature12166]
Kremer, L. S., Danhauser, K., Herebian, D., Ramadza, D. P., Piekutowska-Abramczuk, D., Seibt, A., Muller-Felber, W., Haack T. B., Ploski, R., Lohmeier, K., Schneider, D., Klee, D., and 10 others. NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood. Am. J. Hum. Genet. 99: 894-902, 2016. [PubMed: 27616477] [Full Text: https://doi.org/10.1016/j.ajhg.2016.07.018]
Marbaix, A. Y., Tyteca, D., Niehaus, T. D., Hanson, A. D., Linster, C. L., Van Schaftingen, E. Occurrence and subcellular distribution of the NAD(P)HX repair system in mammals. Biochem. J. 460: 49-58, 2014. [PubMed: 24611804] [Full Text: https://doi.org/10.1042/BJ20131482]
Pronicka, E., Piekutowska-Abramczuk, D., Ciara, E., Trubicka, J., Rokicki, D., Karkucinska-Wieckowska, A., Pajdowska, M., Jurkiewicz, E., Halat, P., Kosinska, J., Pollak, A., Rydzanicz, M., Stawinski, P., Pronicki, M., Krajewska-Walasek, M., Ploski, R. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. J. Transl. Med. 14: 174, 2016. Note: Electronic Article. [PubMed: 27290639] [Full Text: https://doi.org/10.1186/s12967-016-0930-9]
Ritter, M., Buechler, C., Boettcher, A., Barlage, S., Schmitz-Madry, A., Orso, E., Bared, S. M., Schmiedeknecht, G., Baehr, C. H., Fricker, G., Schmitz, G. Cloning and characterization of a novel apolipoprotein A-I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or ApoA-I. Genomics 79: 693-702, 2002. [PubMed: 11991719] [Full Text: https://doi.org/10.1006/geno.2002.6761]
Spiegel, R., Shaag, A., Shalev, S., Elpeleg, O. Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy. Neurogenetics 17: 187-190, 2016. [PubMed: 27122014] [Full Text: https://doi.org/10.1007/s10048-016-0483-3]