Klöckner, Chiara;
Murray, J Pedro Fernandez;
Tavasoli, Mahtab;
Sticht, Heinrich;
Stoltenburg-Didinger, Gisela;
Scholle, Leila Motlagh;
Bakhtiari, Somayeh;
... Platzer, Konrad; + view all
(2022)
Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.
Brain
, 145
(6)
pp. 1916-1923.
10.1093/brain/awac074.
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Abstract
The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.
| Type: | Article |
|---|---|
| Title: | Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awac074 |
| Publisher version: | https://doi.org/10.1093/brain/awac074 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Kennedy pathway, choline kinase alpha, epilepsy, exome sequencing, neurodevelopmental disorder |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144526 |
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