RRC ID 70732
Author Goodman LD, Cope H, Nil Z, Ravenscroft TA, Charng WL, Lu S, Tien AC, Pfundt R, Koolen DA, Haaxma CA, Veenstra-Knol HE, Wassink-Ruiter JSK, Wevers MR, Jones M, Walsh LE, Klee VH, Theunis M, Legius E, Steel D, Barwick KES, Kurian MA, Mohammad SS, Dale RC, Terhal PA, van Binsbergen E, Kirmse B, Robinette B, Cogné B, Isidor B, Grebe TA, Kulch P, Hainline BE, Sapp K, Morava E, Klee EW, Macke EL, Trapane P, Spencer C, Si Y, Begtrup A, Moulton MJ, Dutta D, Kanca O, Undiagnosed Diseases Network, Wangler MF, Yamamoto S, Bellen HJ, Tan QK.
Title TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.
Journal Am J Hum Genet
Abstract Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.
Volume 108(9)
Pages 1669-1691
Published 2021-9-2
DOI 10.1016/j.ajhg.2021.06.019
PII S0002-9297(21)00267-6
PMID 34314705
PMC PMC8456166
MeSH Alleles Amino Acid Sequence Animals Developmental Disabilities / genetics* Developmental Disabilities / metabolism Developmental Disabilities / pathology Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism Eye Diseases, Hereditary / genetics* Eye Diseases, Hereditary / metabolism Eye Diseases, Hereditary / pathology Female Gene Dosage Gene Expression Regulation, Developmental Genome, Human Humans Infant Infant, Newborn Intellectual Disability / genetics* Intellectual Disability / metabolism Intellectual Disability / pathology Karyopherins / antagonists & inhibitors Karyopherins / genetics* Karyopherins / metabolism Male Musculoskeletal Abnormalities / genetics* Musculoskeletal Abnormalities / metabolism Musculoskeletal Abnormalities / pathology Mutation Neurons / metabolism Neurons / pathology RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Sequence Alignment Sequence Homology, Amino Acid Whole Genome Sequencing beta Karyopherins / genetics* beta Karyopherins / metabolism ran GTP-Binding Protein / genetics* ran GTP-Binding Protein / metabolism
IF 10.502
Drosophila DGRC#205260