Resolution of SLC6A1 variable expressivity in a multi-generational family using deep clinical phenotyping and Drosophila models DOI Creative Commons

Kristy L. Jay,

Nikhita Gogate,

Kim Ezell

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 28, 2024

Abstract Purpose Variants in SLC6A1 result a rare neurodevelopmental disorder characterized by variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. haploinsufficiency has been confirmed as the predominant pathway SLC6A1- related disorders (NDDs), however, molecular mechanism underlying remains unclear. Methods Here, through work Undiagnosed Diseases Network, we identify an undiagnosed individual with inherited p.(A334S) variant uncertain significance. To resolve this case better understand expressivity , assess phenotypes proband cohort cases diagnosed NDDs. We then create allelic series Drosophila melanogaster to functionally characterize variants. Results significant overlap between unsolved NDDs find mild severe associated missense confirm flies expressing variants consistent partial loss-of-function mechanism. Conclusion conclude that is hypomorphic allele begin elucidate variability -related These insights will inform diagnosis, prognosis, treatment therapeutic design for those living

Язык: Английский

Gene-replacement therapy in neurodevelopmental disorders: progress and challenges DOI Creative Commons
Holger Lerche, Ulrike B. S. Hedrich, Thomas V. Wuttke

и другие.

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(3)

Опубликована: Фев. 2, 2025

Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is main GABA transporter brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require delivery genes specific types neurons or areas likely during certain time points. In this issue JCI, Guo colleagues from Gray lab evaluated two promoters, three injection modalities, various timing for replacement GAT1 via AAV type 9 heterozygous homozygous knockout mouse models. Intrathecal administration vectors containing either promoter at postnatal day 5 achieved high expression was best tolerated approach. Notably, gene-replacement therapy failed later disease stages, suggesting importance early gene reconstitution confirming metabolism brain development.

Язык: Английский

Процитировано

1
Behavioral, neurodevelopmental profile, and epilepsy trajectory in two series of SLC6A1-NDD: a retrospective study with comprehensive assessment, and a participatory database study DOI
Sarah Baer,

Mathieu Rebert,

Pauline Burger

и другие.

European Journal of Paediatric Neurology, Год журнала: 2025, Номер 54, С. 121 - 129

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

1
A transporter’s doom or destiny: SLC6A1 in health and disease, novel molecular targets and emerging therapeutic prospects DOI Creative Commons
Nikita Shah, Ameya Kasture, Florian P. Fischer

и другие.

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Авг. 29, 2024

As the first member of solute carrier 6 (SLC6) protein family, γ-aminobutyric acid (GABA) transporter 1 (GAT1, SLC6A1 ), plays a pivotal role in uptake GABA from synaptic cleft into neurons and astrocytes. This process facilitates subsequent storage presynaptic vesicles. The human gene is highly susceptible to missense mutations, leading severe clinical outcomes, such as epilepsy, afflicted patients. molecular mechanisms -associated disorders are discerned some degree; many mutations now known impair folding, consequently fail reach plasma membrane. Inherently, once inside endoplasmic reticulum (ER), GAT1 abides by complex cascade events that enable efficient intracellular trafficking. involves association with specialized chaperones responsible for steering folding process, oligomerization, sorting through Golgi apparatus, ultimately delivery cell surface. entire subject stringent quality control at multiple checkpoints. While majority existing loss-of-function variants interfere membrane targeting, certain mutants retain abundant surface expression. In either scenario, suppressed activity disrupts GABAergic neurotransmission, preceding disease manifestation individuals harboring these mutations. nervous system enthralling calls systematic, groundbreaking research efforts dissect precise factors associated onset neurological disorders, uncover additional non-canonical therapeutic targets. Recent has given hope misfolded variants, which can be salvaged small molecules, i.e., chemical pharmacological chaperones, acting on upstream targets secretory pathway. We here highlight significance pharmacochaperoning strategy treatment -related disorders.

Язык: Английский

Процитировано

3
AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice DOI Creative Commons

Weirui Guo,

Matthew Rioux,

Frances C. Shaffo

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 135(3)

Опубликована: Ноя. 26, 2024

The solute carrier family 6 member 1 (SLC6A1) gene encodes the γ-aminobutyric acid (GABA) transporter GAT-1, deficiency of which is associated with infantile encephalopathy intellectual disability. We designed 2 AAV9 vectors, either JeT or MeP promoter, and conducted preclinical therapy studies using heterozygous homozygous Slc6a1-KO mice at different developmental ages various routes administration. Neonatal intracerebroventricular administration vector resulted in significantly normalized EEG patterns Slc6a1-/- Slc6a1+/- as well improvement several behavioral phenotypes mice. However, some mortality adverse effects were observed neonatal-treated Intrathecal P5 mice, but treatment only rescued nest building without impact on EEG. Both vectors tolerated all treated later (including WT mice), up to year after injection. Overall, our data demonstrate compelling efficacy when are an early development age. also identified that outside neonatal window, severe KO model more refractory treatment, whereas treatments genotypically match human patients, have stronger benefits.

Язык: Английский

Процитировано

2
Analysis of exome sequencing data implicates rare coding variants in STAG1 and ZNF136 in schizophrenia DOI Creative Commons
Sophie L. Chick, Peter Holmans, Detelina Grozeva

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 16, 2024

Abstract Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 at exome-wide levels of significance. To increase power for gene discovery, we analysed exome-sequencing data rare a new sample 4,650 cases and 5,719 controls, combined these with published sequencing total 28,898 cases, 103,041 controls 3,444 proband-parent trios. Novel associations were identified STAG1 ZNF136 significance six additional false discovery rate 5%. Among genes, SLC6A1 KLC1 are associated damaging missense alone. Four the eight novel also enriched other developmental psychiatric disorders. Moreover, fine-mapped common variant signals schizophrenia. These findings provide insights into neurobiology schizophrenia, including an aetiological role disrupted chromatin organisation.

Язык: Английский

Процитировано

1
Abnormal Weakening of DNA Methylation around the SLC6A1 Gene Promoter in Temporal Lobe Epilepsy DOI Creative Commons
Hua Tao,

Zhengjuan Wu,

Yang Liu

и другие.

Journal of Integrative Neuroscience, Год журнала: 2024, Номер 23(9)

Опубликована: Сен. 24, 2024

Background: The solute carrier (SLC) superfamily, which transports solutes across biological membranes, includes four members (SLC2A1, SLC6A1, SLC9A64, and SLC35A2) that have been linked to epilepsy. This study sought examine the DNA methylation patterns near promoters of these genes in temporal lobe epilepsy (TLE), as is a crucial epigenetic modification can impact gene expression. Methods: comprised 38 individuals with TLE healthy controls. Methylation experiments were performed using peripheral blood, while demethylation carried out SH-SY5Y cells inhibitor decitabine. Results: A significant difference was observed rate SLC6A1 between patients controls, showing lower (4.81% vs. 5.77%, p = 0.0000), remained even after Bonferroni correction (p 0.0000). Based on hypomethylated TLE, predictive model established showed promise distinguishing calibrating TLE. In group, there differences rates young older controls (4.42% 5.22%, 0.0004). similar trend 0.0436) noted adjusting for sex, age at onset, drug response. addition, found had silencing expression cells, treated decitabine set dose gradient. Conclusions: evidence suggests may stimulate transcription however, further investigation necessary confirm exact mechanism.

Язык: Английский

Процитировано

0
Resolution of SLC6A1 variable expressivity in a multi-generational family using deep clinical phenotyping and Drosophila models DOI Creative Commons

Kristy L. Jay,

Nikhita Gogate,

Kim Ezell

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 28, 2024

Abstract Purpose Variants in SLC6A1 result a rare neurodevelopmental disorder characterized by variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. haploinsufficiency has been confirmed as the predominant pathway SLC6A1- related disorders (NDDs), however, molecular mechanism underlying remains unclear. Methods Here, through work Undiagnosed Diseases Network, we identify an undiagnosed individual with inherited p.(A334S) variant uncertain significance. To resolve this case better understand expressivity , assess phenotypes proband cohort cases diagnosed NDDs. We then create allelic series Drosophila melanogaster to functionally characterize variants. Results significant overlap between unsolved NDDs find mild severe associated missense confirm flies expressing variants consistent partial loss-of-function mechanism. Conclusion conclude that is hypomorphic allele begin elucidate variability -related These insights will inform diagnosis, prognosis, treatment therapeutic design for those living

Язык: Английский

Процитировано

0