Unknown

Dataset Information

0

A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.


ABSTRACT: 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.

SUBMITTER: Parnell E 

PROVIDER: S-EPMC9751355 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

altmetric image

Publications

A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

Parnell Euan E   Voorn Roos A RA   Martin-de-Saavedra M Dolores MD   Loizzo Daniel D DD   Dos Santos Marc M   Penzes Peter P  

Frontiers in molecular neuroscience 20221201


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 reducti  ...[more]

Similar Datasets

| S-EPMC7056728 | biostudies-literature
| S-EPMC6531540 | biostudies-literature
| S-EPMC5002929 | biostudies-literature
| S-EPMC8567516 | biostudies-literature
| S-EPMC11228517 | biostudies-literature
| S-EPMC10586195 | biostudies-literature
| S-EPMC6609509 | biostudies-literature
| S-EPMC9235849 | biostudies-literature
| S-EPMC4951812 | biostudies-literature
| S-EPMC8452856 | biostudies-literature