Dataset Information

A Mouse Mutation That Dysregulates Neighboring Galnt17 and Auts2 Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

ABSTRACT: AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of AUTS2, GALNT17, which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of AUTS2-linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation's selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human "AUTS2 syndrome" and the wide array of neurodevelopmental disorders linked to variance in this genomic region.

SUBMITTER: Weisner PA

PROVIDER: S-EPMC6829118 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A Mouse Mutation That Dysregulates Neighboring Galnt17 and Auts2 Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

Weisner P Anne PA Chen Chih-Ying CY Sun Younguk Y Yoo Jennifer J Kao Wei-Chun WC Zhang Huimin H Baltz Emily T ET Troy Joseph M JM Stubbs Lisa L

G3 (Bethesda, Md.) 20191105 11

AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could a ...[more]

PMID: 31554716

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Project description:Mutations in the NPHS2 gene, encoding podocin, cause hereditary nephrotic syndrome. The most common podocin mutation, R138Q, is associated with early disease onset and rapid progression to end-stage renal disease. Knock-in mice carrying a R140Q mutation, the mouse analogue of human R138Q, show developmental arrest of podocytes and lethal renal failure at neonatal age. Here we created a conditional podocin knock-in model named NPHS2 R140Q/-, using a tamoxifen-inducible Cre recombinase, which permits to study the effects of the mutation in postnatal life. Within the first week of R140Q hemizygosity induction the animals developed proteinuria, which peaked after 4-5 weeks. Subsequently the animals developed progressive renal failure, with a median survival time of 12 (95% CI: 11-13) weeks. Foot process fusion was observed within one week, progressing to severe and global effacement in the course of the disease. The number of podocytes per glomerulus gradually diminished to 18% compared to healthy controls 12-16 weeks after induction. The fraction of segmentally sclerosed glomeruli was 25%, 85% and 97% at 2, 4 and 8 weeks, respectively. Severe tubulointerstitial fibrosis was present at later disease stage and was correlated quantitatively with the level of proteinuria at early disease stages. While R140Q podocin mRNA expression was elevated, protein abundance was reduced by more than 50% within one week following induction. Whereas miRNA21 expression persistently increased during the first 4 weeks, miRNA-193a expression peaked 2 weeks after induction. In conclusion, the inducible R140Q-podocin mouse model is an auspicious model of the most common genetic cause of human nephrotic syndrome, with a spontaneous disease course strongly reminiscent of the human disorder. This model constitutes a valuable tool to test the efficacy of novel pharmacological interventions aimed to improve podocyte function and viability and attenuate proteinuria, glomerulosclerosis and progressive renal failure.

Dataset Information

A Mouse Mutation That Dysregulates Neighboring Galnt17 and Auts2 Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

Publications

A Mouse Mutation That Dysregulates Neighboring <i>Galnt17</i> and <i>Auts2</i> Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

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