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FB2026_01
,
released March 12, 2026
A group of individuals exhibiting developmental delays and feeding difficulties during infancy or in early childhood were assessed by whole-exome sequencing (WES). Fifteen were found to carry a potentially pathogenic, heterozygous coding variant in TNPO2. Trio (proband and both biological parents) sequencing revealed that in all but one case the TNPO2 variants are de novo; for the one exception, the mother was found to be low-level mosaic.
TNPO2 encodes a protein involved in nuclear protein import as a nuclear transport receptor; it is paralogous to a very similar gene, TNPO1. Many proteins have been identified as cargoes shuttled by TNPO1 and/or TNPO2. There is one high-scoring ortholog of TNPO2 and TNPO1 in Drosophila, Dmel\Tnpo, for which RNAi targeting constructs and alleles caused by insertional mutagenesis have been generated.
Both human genes have been introduced into flies. A UAS construct carrying a wild-type human Hsap\TNPO2 gene has been characterized in the context of this disease model. Hsap\TNPO1 has been introduced into flies as part of investigations of the role of nuclear-import receptors in several neurodegenerative disorders caused by RNA-binding proteins (FBhh0000018, FBhh0000298).
Animals homozygous or hemizygous for loss-of-function mutations of Dmel\Tnpo typically die during the second or third larval instar stages. Tnpo is primarily expressed in a subset of neurons in the CNS, including mushroom body neurons of the brain. Phenotypes caused by decreasing Tnpo activity are dosage dependent with greater reductions in Tnpo activity causing more severe defects; however, upregulation of Tnpo causes similar defects as Tnpo loss. Mutations analogous to variants implicated in this disease have been introduced into the fly gene; see the 'Disease-Implicated Variants' table, below. The severity of the variants tested appears to correlate with their positions within the protein.
[updated Sep. 2021 by FlyBase; FBrf0222196]
[INTELLECTUAL DEVELOPMENTAL DISORDER WITH HYPOTONIA, IMPAIRED SPEECH, AND DYSMORPHIC FACIES; IDDHISD](https://omim.org/entry/619556)
[TRANSPORTIN 2; TNPO2](https://omim.org/entry/603002)
All identified individuals present with global developmental delays. Speech abilities and intelligence are typically more impaired than motor abilities. Other common features include variable dysmorphic features, ophthalmologic abnormalities (primarily strabismus), muscle tone abnormalities (primarily hypotonia), movement/neurological disorders, and neurological features. (Goodman et al., 2021; pubmed:34314705)
Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD) is characterized by global developmental delay with impaired intellectual development and poor or absent speech, hypotonia, ophthalmologic abnormalities, and nonspecific dysmorphic features. Some affected individuals have seizures, and a few have involvement of other organ systems (Goodman et al., 2021; pubmed:34314705). [from MIM:619556; 2021.10.16]
intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD) is caused by heterozygous mutation in the TNPO2 gene. [from MIM:619556; 2021.10.16]
TNPO2 encodes a protein involved in nuclear protein import as a nuclear transport receptor; it serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. [Gene Cards, TNPO2; 2021.09.12]
Many to many: 2 human genes to 2 Drosophila genes.