Biology subjects

Depienne, C.

Publications and source records attributed to Depienne, C..

4 recordsLinked to original sources

bioRxiv2026

Comprehensive classification of HCN1 variants linked to neurodevelopmental disorders with and without epilepsy

Hyperpolarization-activated cyclic nucleotide-gated 1 channels (HCN1) mediate the Ih cationic current and play a central role in regulating neuronal excitability and synaptic integration. HCN1 is predominantly expressed in the neocortex and hippocampus. Pathogenic variants in HCN1 have been increasingly identified in individuals presenting with a broad spectrum of epileptic disorders, ranging from severe developmental and epileptic encephalopathy (DEE) to milder epilepsies. Here, we used patch-clamp electrophysiology in combination with confocal imaging in HEK293 cells to functionally characterize 43 HCN1 variants found in patients presenting with neurodevelopmental disorders, with or without epilepsy. Based on their biophysical properties, we defined four functional classes: (I) low or no current, (II) hyperpolarizing (i.e. left) shift in voltage dependence, (III) depolarizing (i.e. right) shift in voltage dependence, and (IV) generation of an instantaneous current. Integration of this functional classification with detailed clinical data from a cohort of 49 patients revealed a striking genotype-phenotype correlation. Loss-of-function variants were strongly enriched among individuals without epilepsy or with milder generalized phenotypes, whereas gain-of-function and mixed variants were predominantly associated with epilepsy, including all cases of DEE. Notably, non-epileptic cases clustered within a subgroup of loss-of-function variants affecting the selectivity filter. We further show that allosteric modulators, including the peptides NB6 and TRIP8bnano and the small molecule J&J12e, normalize the functional properties of mutant HCN1 channels in three classes. These findings establish a clinically relevant framework for interpreting HCN1 gain- and loss-of-function variants suggesting that the direction of channel dysfunction is a major determinant of epilepsy risk and severity.

pathology↗

bioRxiv2021

Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR signaling

PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.

genetics↗

bioRxiv2020

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

genetics↗

bioRxiv2018

Identification of SMARCD1 as a syndromic intellectual disability gene that is required for memory and context-dependent regulation of neuronal genes in Drosophila

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause syndromic intellectual disability (ID). Here, we report on 5 individuals with mutations in the SMARCD1 gene, presenting with ID, developmental delay, hypotonia, feeding difficulties, and small extremities. The mutations were proven to be de novo in 4 of the 5 individuals. Mutations in other SWI/SNF components cause Coffin-Siris, Nicolaides-Baraitser, or other syndromic ID disorders. Although the individuals presented here have some clinical overlap with these disorders, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify SMARCD1 mutations as a novel cause of ID, and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.

genetics↗