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Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

ABSTRACT: Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients' variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

SUBMITTER: Gozzelino L

PROVIDER: S-EPMC9337808 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

Gozzelino Luca L Kochlamazashvili Gaga G Baldassari Sara S Mackintosh Albert Ian AI Licchetta Laura L Iovino Emanuela E Liu Yu Chi YC Bennett Caitlin A CA Bennett Mark F MF Damiano John A JA Zsurka Gábor G Marconi Caterina C Giangregorio Tania T Magini Pamela P Kuijpers Marijn M Maritzen Tanja T Norata Giuseppe Danilo GD Baulac Stéphanie S Canafoglia Laura L Seri Marco M Tinuper Paolo P Scheffer Ingrid E IE Bahlo Melanie M Berkovic Samuel F SF Hildebrand Michael S MS Kunz Wolfram S WS Giordano Lucio L Bisulli Francesca F Martini Miriam M Haucke Volker V Hirsch Emilio E Pippucci Tommaso T

Brain : a journal of neurology 20220701 7

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients' variants act as loss-of-function alleles, leading to imp ...[more]

PMID: 35786744

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Project description:Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.

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Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

Publications

Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

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