Alternative titles; symbols
HGNC Approved Gene Symbol: ZNHIT3
SNOMEDCT: 442511009;
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:36,486,681-36,499,312 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | PEHO syndrome | 260565 | Autosomal recessive | 3 |
The ZNHIT3 gene encodes a nuclear zinc finger protein implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly, and thus it may play a role in preribosomal RNA processing (summary by Anttonen et al., 2017).
The thyroid hormone receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. They must specifically interact with a number of proteins as they progress from their initial translation and nuclear translocation to heterodimerization with retinoid X receptors (RXRs), functional interactions with other transcription factors and the basic transcriptional apparatus, and eventually, degradation. To help elucidate the mechanisms that underlie the transcriptional effects and other potential functions of TRs, Lee et al. (1995) used the yeast interaction trap, a version of the yeast 2-hybrid system, to identify proteins that specifically interact with the ligand-binding domain of rat TR-beta (THRB; 190160). They isolated HeLa cell cDNAs encoding several different TR-interacting proteins (TRIPs), including TRIP3. A region of TRIP3 that includes a number of negatively charged residues shows similarity to several short regions of the Drosophila CUT protein, a homeodomain-containing transcription factor. Northern blot analysis detected a 1.1-kb TRIP3 transcript in all tissues examined.
Anttonen et al. (2017) found expression of the Znhit3 gene in mouse fetal cerebellar granule cell precursors, in proliferating and postmitotic postnatal granule cells, and in mature postnatal Purkinje cells in the cerebellum.
Lee et al. (1995) found that TRIP3 interacted with rat Thrb only in the presence of thyroid hormone. It also showed a ligand-dependent interaction with RXR-alpha (RXRA; 180245), but did not interact with the glucocorticoid receptor (NR3C1; 138040) under any condition.
In 24 patients of Finnish descent with PEHO syndrome (260565), Anttonen et al. (2017) identified a homozygous missense mutation in the ZNHIT3 gene (S31L; 604500.0001). The mutation in the first 3 patients was found by a combination of homozygosity mapping and Sanger sequencing of candidate genes; the mutation in 1 patient was found by whole-exome sequencing. The mutation segregated with the disorder in all families. Cellular knockdown of Znhit3 in mouse cerebellar granule cells sensitized the neurons to death and impaired their migration.
Anttonen et al. (2017) found that morpholino knockdown of the znhit3 gene in zebrafish embryos resulted in microcephaly, cerebellar atrophy, and pericardiac edema. Morphant animals and CRISPR mutants had depletion of neuronal axons across the midline as well as the caudolateral portion of the cerebellum, which represented an aberrant granule cell phenotype. These defects could be rescued by expression of human wildtype ZNHIT3.
In 24 patients of Finnish descent with PEHO syndrome (260565), Anttonen et al. (2017) identified a homozygous c.92C-T transition (c.92C-T, NM_004773.3) in the ZNHIT3 gene, resulting in a ser31-to-leu (S31L) substitution at a highly conserved residue in the zinc finger-HIT domain located next to one of the zinc-coordinating cysteines. The mutation in the first 3 patients was found by a combination of homozygosity mapping and Sanger sequencing of candidate genes; the mutation in 1 patient was found by whole-exome sequencing. The mutation segregated with the disorder in all families. It was found in heterozygous state at a low frequency in the ExAC database (0.07%), and at a slightly higher frequency (0.92%) among Finnish individuals. The mutant protein was unstable and underwent more rapid proteasomal degradation compared to wildtype. It also tended to form large nuclear aggregates, suggesting impaired folding with subsequent degradation. Injection of the S31L mutant was unable to rescue the microcephaly, cerebellar atrophy, and pericardiac edema of zebrafish embryos with morpholino knockdown of the znhit3 gene, suggesting that the mutation results in a loss of function.
Anttonen, A.-K., Laari, A., Kousi, M., Yang, Y. J., Jaaskelainen, T., Somer, M., Siintola, E., Jakkula, E., Muona, M., Tegelberg, S., Lonnqvist, T., Pihko, H., and 10 others. ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss. Brain 140: 1267-1279, 2017. [PubMed: 28335020] [Full Text: https://doi.org/10.1093/brain/awx040]
Lee, J. W., Choi, H.-S., Gyuris, J., Brent, R., Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Molec. Endocr. 9: 243-254, 1995. [PubMed: 7776974] [Full Text: https://doi.org/10.1210/mend.9.2.7776974]