A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology
The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missens...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-12-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.994513/full |
| _version_ | 1811191022574632960 |
|---|---|
| author | Euan Parnell Roos A. Voorn M. Dolores Martin-de-Saavedra Daniel D. Loizzo Marc Dos Santos Peter Penzes Peter Penzes Peter Penzes |
| author_facet | Euan Parnell Roos A. Voorn M. Dolores Martin-de-Saavedra Daniel D. Loizzo Marc Dos Santos Peter Penzes Peter Penzes Peter Penzes |
| author_sort | Euan Parnell |
| collection | DOAJ |
| description | The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay. |
| first_indexed | 2024-04-11T14:58:56Z |
| format | Article |
| id | doaj.art-f990da43badb401a8a6935dc1692b97f |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-11T14:58:56Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-f990da43badb401a8a6935dc1692b97f2022-12-22T04:17:03ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-12-011510.3389/fnmol.2022.994513994513A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphologyEuan Parnell0Roos A. Voorn1M. Dolores Martin-de-Saavedra2Daniel D. Loizzo3Marc Dos Santos4Peter Penzes5Peter Penzes6Peter Penzes7Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Biochemistry and Molecular Biology, School of Pharmacy, Instituto Universitario de Investigación en Neuroquímica, Complutense University of Madrid, Madrid, SpainDepartment of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesCentre for Autism and Neurodevelopment, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesThe Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay.https://www.frontiersin.org/articles/10.3389/fnmol.2022.994513/fulldevelopmental delayneuronspineNMDArneurodevelopment |
| spellingShingle | Euan Parnell Roos A. Voorn M. Dolores Martin-de-Saavedra Daniel D. Loizzo Marc Dos Santos Peter Penzes Peter Penzes Peter Penzes A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology Frontiers in Molecular Neuroscience developmental delay neuron spine NMDAr neurodevelopment |
| title | A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology |
| title_full | A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology |
| title_fullStr | A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology |
| title_full_unstemmed | A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology |
| title_short | A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology |
| title_sort | developmental delay linked missense mutation in kalirin 7 disrupts protein function and neuronal morphology |
| topic | developmental delay neuron spine NMDAr neurodevelopment |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.994513/full |
| work_keys_str_mv | AT euanparnell adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT roosavoorn adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT mdoloresmartindesaavedra adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT danieldloizzo adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT marcdossantos adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes adevelopmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT euanparnell developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT roosavoorn developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT mdoloresmartindesaavedra developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT danieldloizzo developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT marcdossantos developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology AT peterpenzes developmentaldelaylinkedmissensemutationinkalirin7disruptsproteinfunctionandneuronalmorphology |