Alternative titles; symbols
HGNC Approved Gene Symbol: NKX6-2
SNOMEDCT: 1217379007;
Cytogenetic location: 10q26.3 Genomic coordinates (GRCh38) : 10:132,783,181-132,786,147 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.3 | Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy | 617560 | Autosomal recessive | 3 |
The NKX6-2 gene encodes a member of the NKX protein family of transcription factors, which have established roles during the development of an organism (summary by Chelban et al., 2017).
Homeobox genes act as master genes that control pattern formation and positional information during embryonic development. In the adult, they are thought to maintain the differentiated states of cell populations and to direct the renewal of specific cell types. While homeobox genes are widely expressed in the developing vertebrate nervous system, only a few, including NKX6B, continue to be expressed in the adult brain (summary by Lee et al., 2001).
Nkx6.2 was isolated in mouse by Komuro et al. (1993). Expression of Nkx6.2 appeared to be tissue specific and developmentally regulated. In day-18 mouse embryos, it was expressed in part of the forebrain as well as in mid- and hindbrain, whereas in the adult CNS, expression was most abundant in areas rich in oligodendrocyte cell bodies and astrocytes. Together with DNA binding assays, these expression studies suggested that the Nkx6.2 gene product may be important for differentiated oligodendrocyte function and in the regulation of myelin gene expression.
Lee et al. (2001) cloned and characterized NKX6B, the human homolog of mouse Nkx6.2. The predicted 277-amino acid NKX6B protein shares 97% identity with mouse Nkx6.2 and 52% homology with NKX6A (NKX6-1; 602563). Northern blot analysis showed that NKX6B expression is tightly controlled in a tissue-specific fashion, with highest expression in brain.
Using immunohistochemistry and in situ hybridization, Vallstedt et al. (2001) detected expression of Nkx6-2 first in the caudal neural tube in a broad ventral domain at approximately embryonic day 8.5. Nkx6-2 was expressed predominantly within the dorsal progenitor p1 domain and more weakly in the p0 domain.
In embryonic mice, Southwood et al. (2004) found expression of Nkx6-2 in cranial nerves, interneuron precursors, and motoneurons that extend axons into the periphery. Nkx6-2 continued to be expressed in the nucleus of oligodendrocytes in adult mouse brain.
By DNA sequence analysis of an 11-kb genomic fragment, Lee et al. (2001) demonstrated that the NKX6B gene spans 1.2 kb and contains 3 exons.
Using STS content mapping and radiation hybrid analysis, Lee et al. (2001) mapped NKX6B gene to 10q26, a region where loss of heterozygosity has frequently been observed in various malignant brain tumors. Lee et al. (2001) suggested that NKX6B may be a tumor suppressor gene for brain tumors, particularly for oligodendrogliomas.
Komuro et al. (1993) mapped the mouse Nkx6b gene to the distal portion of chromosome 7.
Using in silico analysis, gene-regulatory networks, and coexpression data in humans, Chelban et al. (2017) concluded that NKX6-2 is involved in the genesis and development of oligodendrocytes.
In 7 patients from 3 unrelated families with autosomal recessive spastic ataxia-8 (SPAX8; 617560), Chelban et al. (2017) identified homozygous mutations in the NKX6-2 gene (K41X, 605955.0001 and L163V, 605955.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the families. Cells from a patient with the nonsense mutation showed absence of the truncated protein, consistent with a complete loss of function; functional studies and studies of patients cells with the missense mutation were not performed.
Dorboz et al. (2017) identified biallelic mutations in the NKX6-2 gene in 5 patients, including 2 sib pairs, from 3 unrelated families with SPAX8. The patients from families 1 and 2 had homozygous mutations (605955.0003 and 605955.0004) and the sibs from family 3 had compound heterozygous mutations (605955.0005 and 605955.0006). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies in patient cells were not performed.
Vallstedt et al. (2001) obtained Nkx6-2 -/- mice at the expected mendelian ratio, and Nkx6-2 -/- mice survived through adulthood. Examination of progenitor cell fate in embryonic Nkx6-2 -/- spinal cord suggested that Nkx6-2 in p1 progenitor cells promoted generation of V1 interneurons and helped to suppress V0 interneurons. Use of Nkx6-1/Nkx6-2 compound mutant embryos revealed that Nkx6-1 and Nkx6-2 had an equivalent inhibitory influence of generation of V0 interneurons. Nkx6-1 and Nkx6-2 also had additive effects, with higher or lower total Nkx6 content directing progenitors to different interneuron or motor neuron cell fates.
Southwood et al. (2004) found that Nkx6-2-null mice had deficits in motor coordination and nerve conduction in the central nervous system. These abnormalities were associated with myelination defects at paranodal junctions, particularly in the optic nerve, and aberrant expression of downstream genes involved in cytoskeletal and cell adhesion functions. The findings suggested a role for Nkx6-2 in the regulation of axon-glial interactions at myelin paranodes.
In 5 patients from 2 unrelated consanguineous families with spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560), Chelban et al. (2017) identified a homozygous c.121A-T transversion (c.121A-T, NM_177400.2) in exon 1 of the NKX6-2 gene, resulting in a lys41-to-ter (K41X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in both families. It was not found in public databases or in an in-house database of 1,284 ethnically matched exomes. One family was of North Indian descent and the other was of Kenyan and Tanzanian descent; haplotype analysis indicated a founder effect. Analysis of patient cells showed absence of the mutant protein, consistent with a complete loss of function.
In 2 sibs, born of consanguineous Saudi Arabian parents with autosomal recessive spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560), Chelban et al. (2017) identified a homozygous c.487C-G transversion (c.487C-G, NM_177400.2) in the NKX6-2 gene, resulting in a leu163-to-val (L163V) substitution at a highly conserved residue in the consensus homeobox domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. It was not found in the ExAC database and was present only once in heterozygous state in 2,363 control Saudi exomes. Functional studies of the variant and studies of patient cells were not performed.
In a male patient, born to consanguineous parents (family 1), with spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560), Dorboz et al. (2017) identified homozygosity for a c.606delinsTA (c.606delinsTA, NM_177400.2) mutation in the NKX6-2 gene, predicted to result in a frameshift and premature termination (Lys202AsnfsTer) in the homeobox domain. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was present in the carrier state in the parents. The mutation was not present in the dbSNP (build 147) and ExAC (v.0.3) databases or in an in-house database of over 700 population-matched exomes.
In a brother and sister, born to consanguineous Moroccan parents (family 2), with spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560), Dorboz et al. (2017) identified homozygosity for a c.565G-T transversion (c.565G-T, NM_177400.2) in the NKX6-2 gene, resulting in a glu189-to-ter (E189X) substitution in the homeobox domain. The mutation, which was identified by SNP-based homozygosity mapping and whole-exome sequencing, was present in the carrier state in the parents and an unaffected sib. The mutation was not present in public databases.
In 2 brothers, born to nonconsanguineous parents (family 3), with spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560), Dorboz et al. (2017) identified compound heterozygous mutations in exon 3 of the NKX6-2 gene, a maternally inherited c.589C-T transition (c.589C-T, NM_177400.2), resulting in a gln197-to-ter (Q197X) substitution, and a paternally inherited c.599G-A transition, resulting in an arg200-to-gln (R200Q; 605955.0006) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present in the carrier state in the parents. Both mutations were in the homeobox domain, and the R200Q mutation was predicted to affect DNA binding.
For discussion of the c.599G-A transition (c.599G-A, NM_177400.2) in the NKX6-2 gene, resulting in an arg200-to-gln (R200Q) substitution, that was identified in compound heterozygous state in 2 sibs with spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8; 617560) by Dorboz et al. (2017), see 605955.0005.
Chelban, V., Patel, N., Vandrovcova, J., Zanetti, M. N., Lynch, D. S., Ryten, M., Botia, J. A., Bello, O., Tribollet, E., Efthymiou, S., Davagnanam, I., SYNAPSE Study Group, Bashiri, F. A., Wood, N. W., Rothman, J. E., Alkuraya, F. S., Houlden, H. Mutations in NKX6-2 cause progressive spastic ataxia and hypomyelination. Am. J. Hum. Genet. 100: 969-977, 2017. [PubMed: 28575651] [Full Text: https://doi.org/10.1016/j.ajhg.2017.05.009]
Dorboz, I., Aiello, C., Simons, C., Stone, R. T., Niceta, M., Elmaleh, M., Abuawad, M., Doummar, D., Bruselles, A., Wolf, N. I., Travaglini, L., Boespflug-Tanguy, O., Tartaglia, M., Vanderver, A., Rodriguez, D., Bertini, E. Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy. Brain 140: 2550-2556, 2017. [PubMed: 28969374] [Full Text: https://doi.org/10.1093/brain/awx207]
Komuro, I., Schalling, M., Jahn, L., Bodmer, R., Jenkins, N. A., Copeland, G. A., Izumo, S. Gtx: a novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells of testis, has a transcriptional repressor activity in vitro for a serum-inducible promoter. EMBO J. 12: 1387-1401, 1993. [PubMed: 8096811] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05783.x]
Lee, S.-H., Davison, J. A., Vidal, S. M., Belouchi, A. Cloning, expression and chromosomal location of NKX6B to 10q26, a region frequently deleted in brain tumors. Mammalian Genome 12: 157-162, 2001. [PubMed: 11210186] [Full Text: https://doi.org/10.1007/s003350010247]
Southwood, C., He, C., Garbern, J., Kamholz, J., Arroyo, E., Gow, A. CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure. J. Neurosci. 24: 11215-11225, 2004. [PubMed: 15601927] [Full Text: https://doi.org/10.1523/JNEUROSCI.3479-04.2004]
Vallstedt, A., Muhr, J., Pattyn, A., Pierani, A., Mendelsohn, M., Sander, M., Jessell, T. M., Ericson, J. Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron 31: 743-755, 2001. [PubMed: 11567614] [Full Text: https://doi.org/10.1016/s0896-6273(01)00412-3]