Alternative titles; symbols
HGNC Approved Gene Symbol: NRDC
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38): 1:51,789,210-51,878,727 (from NCBI)
Endoproteases that activate protein precursors by cleavage at basic residues belong to the 4 classes of proteases: aspartyl, serine, thiol, and metalloenzymes. Pierotti et al. (1994) noted that nardilysin (NRD1; EC 3.4.24.61), a metalloendopeptidase that cleaves peptide substrates at the N terminus of arginine residues in dibasic moieties, had previously been purified from rat testis. By screening a rat testis cDNA library with oligonucleotides based on the sequence of the purified Nrd1 protein, Pierotti et al. (1994) cloned a cDNA encoding Nrd1, called N-arginine dibasic (Nrd) convertase by them. The predicted 1,161-amino acid Nrd1 protein has a calculated molecular mass of 133 kD, consistent with the mass of the largest form of the purified enzyme. Nrd1 contains a putative signal peptide, a 71-residue acidic stretch, and a zinc-binding motif. The amino acid sequence of rat Nrd1 is 31% identical to that of human insulinase (IDE; 146680).
Hospital et al. (1997) cloned cDNAs encoding NRD convertase by screening a human testis cDNA library with a rat Nrd convertase cDNA. They found that NRD convertase is expressed in both human and rat as 2 distinct mRNAs that differ by the presence or absence of a 204-nucleotide in-frame insertion. This insertion adds 68 amino acids between the acidic stretch and the zinc-binding motif. The longer, 3.9-kb human mRNA and the shorter, 3.7-kb human mRNA encode predicted 1,219-amino acid and 1,151-amino acid proteins, respectively. The human NRD convertase proteins are 92% identical to the rat Nrd convertases. Northern blot analysis of rat RNAs showed that Nrd convertase is expressed abundantly in testis and at lower levels in most other tissues.
Fumagalli et al. (1998) cloned a human NRD convertase cDNA encoding a predicted 1,147-amino acid protein. By Northern blot analysis of human RNAs, they found that NRD convertase is expressed as a 3.6-kb transcript primarily in adult heart, skeletal muscle, and testis and at much lower levels in other tissues. During early mouse development, Nrd convertase is expressed almost exclusively in neural tissues.
By fluorescence in situ hybridization, Hospital et al. (1997) mapped the human NRD convertase gene to 1p32.2-p32.1, and Fumagalli et al. (1998) refined the localization to 1p32.2.
Yoon et al. (2017) demonstrated that NRD1 localizes to the mitochondria in both humans and Drosophila. Immunoprecipitation and mass spectrometry studies showed that NRD1 interacts with and recruits multiple mitochondrial chaperones and assists in the folding, stability, and protection of alpha-ketoglutarate dehydrogenase (OGDH; 613022) in the mitochondria. Knockdown studies in Drosophila and mouse cells showed that loss of NRD1 resulted in a dramatic decrease in OGDH activity, and loss of either NRD1 or OGDH resulted in an increase in alpha-ketoglutarate, a substrate for OGDH. The findings suggested that NRD1 is required for the proper function of OGDH. Loss of NRD1 or OGDH was also associated with activation of mTORC1 (601231) and a subsequent reduction in autophagy.
Associations Pending Confirmation
For discussion of a possible association between a neurodegenerative disorder and variation in the NRD1 gene, see 602651.0001.
Ohno et al. (2009) found that Nrd1-null mice showed increased prenatal growth defects and neonatal lethality. Those that survived showed a slowly progressive neurodegenerative disorder with impaired motor activities and cognitive deficits. Mutant mice had small brains and a thin cerebral cortex with less myelinated fibers and thinner myelin sheaths. There was also hypomyelination in the peripheral nervous system. Neuron-specific overexpression of Nrd1 resulted in hypermyelination, suggesting that NRD1 regulates myelination and axonal maturation in the nervous system.
In a forward genetic screen for essential genes required for neuronal function in Drosophila, Yoon et al. (2017) identified the CG2025 gene, which is the homolog of human NRD1. Loss of CG2025 caused pupal lethality as well as a slowly progressive loss of electroretinogram (ERG) function, loss of photoreceptors cells, and impaired synaptic transmission. Expression of human NRD1 could rescue the lethality and the ERG phenotype, indicating that the functions of the proteins are evolutionarily conserved. Nrd1-null flies did not have defects in mitochondrial energy production, but mutant flies and mouse cells lacking Nrd1 showed an accumulation of alpha-ketoglutarate, glutamine, and lysine, suggesting impaired activity of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDHc). These changes were associated with impaired activity of OGDH; knockdown of OGDH resulted in a similar phenotype and metabolic abnormalities. Loss of NRD1 or OGDH was also associated with activation of mTORC1 (601231) and a subsequent reduction in autophagy, and treatment with rapamycin rescued the ERG defect, suggesting that hyperactivation of the mTOR pathway underlies the observed neurodegeneration.
This variant is classified as a variant of unknown significance because its contribution to a neurodegenerative disorder has not been confirmed.
In a 15-year-old boy (CDMD1122), born of consanguineous parents from a remote village in Central America, with severe global developmental delay and progressive neurodegeneration, Yoon et al. (2017) identified a homozygous 2-bp deletion (c.1906_1907delAT, NM_002525.2) in exon 17 of the NRD1 gene, resulting in a frameshift and premature termination (Met636ValfsTer2). The variant, which was found by exome sequencing, segregated with the disorder in the family and was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patient had onset of developmental delay in the first year of life with motor impairment, hypotonia, ataxia, absent speech, seizures, optic atrophy, dysphagia, and microcephaly. Brain imaging showed progressive cortical and cerebellar atrophy. A sib with a similar phenotype had died at 16 months of age.
Fumagalli, P., Accarino, M., Egeo, A., Scartezzini, P., Rappazzo, G., Pizzuti, A., Avvantaggiato, V., Simeone, A., Arrigo, G., Zuffardi, O., Ottolenghi, S., Taramelli, R. Human NRD convertase: a highly conserved metalloendopeptidase expressed at specific sites during development and in adult tissues. Genomics 47: 238-245, 1998. [PubMed: 9479496] [Full Text: https://doi.org/10.1006/geno.1997.5078]
Hospital, V., Prat, A., Joulie, C., Cherif, D., Day, R., Cohen, P. Human and rat testis express two mRNA species encoding variants of NRD convertase, a metalloendopeptidase of the insulinase family. Biochem. J. 327: 773-779, 1997. [PubMed: 9581555] [Full Text: https://doi.org/10.1042/bj3270773]
Ohno, M., Hiraoka, Y., Matsuoka, T., Tomimoto, H., Takao, K., Miyakawa, T., Oshima, N., Kiyonari, H., Kimura, T., Kita, T., Nishi, E. Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system. Nature Neurosci. 12: 1506-1513, 2009. [PubMed: 19935654] [Full Text: https://doi.org/10.1038/nn.2438]
Pierotti, A. R., Prat, A., Chesneau, V., Gaudoux, F., Leseney, A.-M., Foulon, T., Cohen, P. N-Arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. Proc. Nat. Acad. Sci. 91: 6078-6082, 1994. [PubMed: 8016118] [Full Text: https://doi.org/10.1073/pnas.91.13.6078]
Yoon, W. H., Sandoval, H., Nagarkar-Jaiswal, S., Jaiswal, M., Yamamoto, S., Haelterman, N. A., Putluri, N., Putluri, V., Sreekumar, A., Tos, T., Aksoy, A., Donti, T., and 13 others. Loss of nardilysin, a mitochondrial co-chaperone for alpha-ketoglutarate dehydrogenase, promotes mTORC1 activation and neurodegeneration. Neuron 93: 115-131, 2017. [PubMed: 28017472] [Full Text: https://doi.org/10.1016/j.neuron.2016.11.038]