Alternative titles; symbols
HGNC Approved Gene Symbol: CNP
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,966,795-41,977,740 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | ?Leukodystrophy, hypomyelinating, 20 | 619071 | Autosomal recessive | 3 |
Cyclic nucleotide phosphodiesterase is a useful marker of myelin. CNPase is a membrane-bound enzyme found at high concentrations in central nervous system myelin and in the outer segments of photoreceptors in the retina (Vogel and Thompson, 1988). Two proteins with CNP activity are known to exist in brain and lymphoid tissues. They appear to be the products of distinct but related mRNA species. Kurihara et al. (1990) showed that the 2 gene products can arise by translation of 2 mRNAs alternatively spliced from a single transcript. In bovine and human brain, there appears to be a single species of mRNA (Vogel and Thompson, 1988), and the bovine brain and retinal forms of the enzyme appear to be identical in sequence.
By Northern blot analysis, Miyoshi et al. (2001) determined that mouse Cnp1 was expressed as a major 2.5-kb transcript and a minor 2.3-kb transcript. Highest expression was in brain, followed by liver, lung, spleen, and heart, with little to no expression in the other tissues examined.
Bifulco et al. (2002) demonstrated that CNP is firmly associated with tubulin (602529) from brain tissue and thyroid cells. They showed that CNP acts as a microtubule-associated protein in promoting microtubule assembly. This activity was found to reside in the C terminus of the enzyme. The authors concluded that CNP is a membrane-bound microtubule-associated protein that can link tubulin to membranes and may regulate cytoplasmic microtubule distribution.
Douglas et al. (1992) used human CNP cDNAs to isolate genomic clones containing the CNP gene which they found to be 9 kb long, with 4 exons separated by 3 introns. Using human CNP cDNA as probes, Monoh et al. (1993) isolated genomic DNA clones. Restriction mapping and sequence analysis demonstrated that the human CNP gene is about 8.5 kb long. There are 2 transcription start points and, in human brain, 2 forms of CNP mRNA are produced from a single gene by alternative splicing, similar to the mouse.
Miyoshi et al. (2001) determined that the mouse Cnp1 gene contains 4 exons and spans 6.8 kb.
Using cDNA probes corresponding to CNP, Bernier et al. (1988) assigned CNP genes to chromosomes 3 and 11 in the mouse. The gene on chromosome 11 is closely linked to the GFAP locus (137780).
Using a human partial cDNA to clone a genomic library, Douglas et al. (1991, 1992) isolated a clone containing the entire structural gene for human CNPase and constructed primers for polymerase chain reaction (PCR) analysis of a panel of somatic cell hybrids, which showed that only hybrids containing human chromosome 17 produced a PCR product. By fluorescence in situ hybridization, they showed that the gene is located at 17q21. Neither method showed evidence of a gene on human chromosome 1 in an area homologous to chromosome 3 of the mouse.
Sprinkle et al. (1992) confirmed the assignment of CNP to chromosome 17 by PCR used with 2 somatic cell hybrid DNA panels. They identified an intron C-to-T polymorphism at nucleotide 1215 that might be useful in mapping the CNP gene more precisely within chromosome 17. Sprinkle et al. (1993) refined the assignment of CNP on chromosome 17 by a 2-step strategy. First, dot blots containing DNA from the parents of 10 three-generation families were screened to identify informative families. Second, 53 members of 4 selected families were typed at this locus. In these 4 families, 29 sibs carried a total of 84 meiotic breakpoints on chromosome 17. Based on the genotypes observed in these 29 sibs, the CNP gene was localized to a fragment bounded by thyroid receptor A1 (THRA1; 190120) at 17q11.2 and nerve growth factor receptor (NGFR; 162010) at 17q21-q22. The genetic distance separating these flanking loci is approximately 6 cM.
By spot-blot hybridization of flow-sorted human chromosomes, Monoh et al. (1993) demonstrated that the CNP gene is on chromosome 17.
Miyoshi et al. (2001) determined that the mouse Cnp1 gene lies in a tail-to-tail orientation with the Dnajc7 gene (601964) on chromosome 11, downstream of the Stat5b gene (604260).
In a 5-year-old boy, born of consanguineous Omani parents, with hypomyelinating leukodystrophy-20 (HLD20; 619071), Al-Abdi et al. (2020) identified a homozygous missense mutation in the CNP gene (S82L; 123830.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed defects in cytoskeletal organization with abnormal F-actin structure. The authors noted that CNP encodes a major component of myelin and is expressed in myelin-forming oligodendrocytes in the central nervous system.
Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. Lappe-Siefke et al. (2003) showed that Cnp1 is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity, and physical stability of myelin were not altered in these mice. Therefore, by genetic means, the chief function of glia in supporting axonal integrity can be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in the lesions of multiple sclerosis, may suffice to cause secondary axonal loss.
In a 5-year-old boy (15DG2109), born of consanguineous Omani parents, with hypomyelinating leukodystrophy-20 (HLD20; 619071), Al-Abdi et al. (2020) identified a homozygous c.245C-T transition (c.245C-T, NM_033133.4) in exon 2 of the CNP gene, resulting in a ser82-to-leu (S82L) substitution at a highly conserved residue. The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed a significant decrease in protein levels compared to controls, suggesting a loss of function. Patient fibroblasts also showed defects in cytoskeletal organization with abnormal F-actin structure. The patient had normal development until about 16 months of age, when he showed developmental regression with loss of skills, resulting in spastic quadriparesis. He had poor growth with progressive microcephaly; brain imaging showed white matter abnormalities and thin corpus callosum. He died at 5 years of age. The patient had 2 older similarly affected brothers who also died in childhood; genetic studies were not performed on the sibs.
Al-Abdi, L., Al Murshedi, F., Elmanzalawy, A., Al Habsi, A., Helaby, R., Ganesh, A., Ibrahim, N., Patel, N., Alkuraya, F. S. CNP deficiency causes severe hypomyelinating leukodystrophy in humans. Hum. Genet. 139: 615-622, 2020. [PubMed: 32128616] [Full Text: https://doi.org/10.1007/s00439-020-02144-4]
Bernier, L., Colman, D. R., D'Eustachio, P. Chromosomal locations of genes encoding 2-prime,3-prime cyclic nucleotide 3-prime-phosphodiesterase and glial fibrillary acidic protein in the mouse. J. Neurosci. Res. 20: 497-504, 1988. [PubMed: 2903254] [Full Text: https://doi.org/10.1002/jnr.490200414]
Bifulco, M., Laezza, C., Stingo, S., Wolff, J. 2-prime,3-prime-cyclic nucleotide 3-prime-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin. Proc. Nat. Acad. Sci. 99: 1807-1812, 2002. [PubMed: 11842207] [Full Text: https://doi.org/10.1073/pnas.042678799]
Douglas, A. J., Fox, M. F., Abbott, C. M., Hinks, L. J., Sharpe, G., Povey, S., Thompson, R. J. Structure and chromosomal localization of the human 2-prime,3-prime-cyclic nucleotide 3-prime-phosphodiesterase gene. Ann. Hum. Genet. 56: 243-254, 1992. [PubMed: 1360194] [Full Text: https://doi.org/10.1111/j.1469-1809.1992.tb01149.x]
Douglas, A. J., Fox, M. F., Hinks, L. J., Povey, S., Thompson, R. J. Localization of the myelin specific enzyme 2-prime,3-prime-cyclic nucleotide-3-prime-phosphohydrolase to 17q21. (Abstract) Cytogenet. Cell Genet. 58: 2004 only, 1991.
Kurihara, T., Monoh, K., Sakimura, K., Takahashi, Y. Alternative splicing of mouse brain 2-prime,3-prime-cyclic nucleotide 3-prime-phosphodiesterase mRNA. Biochem. Biophys. Res. Commun. 170: 1074-1081, 1990. [PubMed: 2167669] [Full Text: https://doi.org/10.1016/0006-291x(90)90502-e]
Lappe-Siefke, C., Goebbels, S., Gravel, M., Nicksch, E., Lee, J., Braun, P. E., Griffiths, I. R., Nave, K.-A. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genet. 33: 366-374, 2003. [PubMed: 12590258] [Full Text: https://doi.org/10.1038/ng1095]
Miyoshi, K., Cui, Y., Riedlinger, G., Robinson, P., Lehoczky, J., Zon, L., Oka, T., Dewar, K., Hennighausen, L. Structure of the mouse Stat 3/5 locus: evolution from Drosophila to zebrafish to mouse. Genomics 71: 150-155, 2001. [PubMed: 11161808] [Full Text: https://doi.org/10.1006/geno.2000.6433]
Monoh, K., Kurihara, T., Takahashi, Y., Ichikawa, T., Kumanishi, T., Hayashi, S., Minoshima, S., Shimizu, N. Structure, expression and chromosomal localization of the gene encoding human 2-prime,3-prime-cyclic-nucleotide 3-prime-phosphodiesterase. Gene 129: 297-301, 1993. [PubMed: 8392017] [Full Text: https://doi.org/10.1016/0378-1119(93)90283-9]
Sprinkle, T. J., Kouri, R. E., Fain, P. D., Stoming, T. A., Whitney, J. B., III. Chromosomal mapping of the human CNP gene using a meiotic crossover DNA panel, PCR, and allele-specific probes. Genomics 16: 542-545, 1993. [PubMed: 8390968] [Full Text: https://doi.org/10.1006/geno.1993.1227]
Sprinkle, T. J., Lanclos, K. D., Lapp, D. F. Assignment of the human 2-prime,3-prime-cyclic nucleotide 3-prime-phosphohydrolase gene to chromosome 17. Genomics 13: 877-880, 1992. [PubMed: 1322358] [Full Text: https://doi.org/10.1016/0888-7543(92)90174-q]
Vogel, U. S., Thompson, R. J. Molecular structure, localization, and possible functions of the myelin-associated enzyme 2-prime,3-prime-cyclic nucleotide 3-prime-phosphodiesterase. J. Neurochem. 50: 1667-1677, 1988. [PubMed: 2836557] [Full Text: https://doi.org/10.1111/j.1471-4159.1988.tb02461.x]