Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans
| Autor: | Rita Pinto-Costa, Kaining Hu, Xiangbin Ruan, Marni J. Falk, Christopher A. Walsh, Caleb Bupp, Christina Fagerberg, Charlotte Brasch-Andersen, Mónica Mendes Sousa, Lars Kjærsgaard Hansen, Pedro Brites, Cai Qi, Colleen Muraresku, Rebecca D. Ganetzky, Oana Caluseriu, Irena Feng, Dong Li, Rong Zhong, Robert Sean Hill, Jennifer E. Neil, Bowei Kang, Xiaochang Zhang, Ana Costa, Elizabeth J. Bhoj, Kristopher T. Kahle, Hakon Hakonarson |
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| Rok vydání: | 2022 |
| Předmět: |
Pediatrics
medicine.medical_specialty Corpus Callosum Dysgenesis DNA Copy Number Variations business.industry medicine.disease Article Mice Phenotype Intellectual Disability Intellectual disability medicine Animals Humans Agenesis of Corpus Callosum business Genetics (clinical) Hydrocephalus Ventriculomegaly |
| Zdroj: | Qi, C, Feng, I, Costa, A R, Pinto-Costa, R, Neil, J E, Caluseriu, O, Li, D, Ganetzky, R D, Brasch-Andersen, C, Fagerberg, C, Hansen, L K, Bupp, C, Muraresku, C C, Ruan, X, Kang, B, Hu, K, Zhong, R, Brites, P, Bhoj, E J, Hill, R S, Falk, M J, Hakonarson, H, Kahle, K T, Sousa, M M, Walsh, C A & Zhang, X 2022, ' Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans ', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 24, no. 2, pp. 319-331 . https://doi.org/10.1016/j.gim.2021.09.014 Genet Med |
| ISSN: | 1098-3600 |
| DOI: | 10.1016/j.gim.2021.09.014 |
| Popis: | PURPOSE: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes, and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. METHODS: We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA Sequencing, super resolution imaging and immunoblotting. We investigated four variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. RESULTS: We uncovered loss-of-function (LoF) ADD1 variants in four unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, while ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. CONCLUSION: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or intellectual disability. |
| Databáze: | OpenAIRE |
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