<i>GABBR2</i> mutations determine phenotype in rett syndrome and epileptic encephalopathy

Yoo, Yongjin; Jung, Jane; Lee, Yoo Na; Lee, Youngha; Cho, Hyosuk; Na, Eunjung; Hong, Jea Yeok; Kim, Eun Jin; Lee, Jin Sook; Lee, Je-Sang; Hong, Chansik; Park, Soo‐Jin; Wie, Jinhong; Miller, Kathryn; Shur, Natasha; Clow, Cheryl; Ebel, Roseànne S.; DeBrosse, Suzanne D.; Henderson, Lindsay B.; Willaert, Rebecca; Castaldi, Christopher; Tikhonova, Irina; Bilgüvar, Kaya; Mane, Shrikant; Kim, Ki Joong; Hwang, Yong Seung; Lee, Seok-Geun; So, Insuk; Lim, Byung Chan; Choi, Hee Jung; Seong, Jae Young; Shin, Yong Beom; Jung, Hosung; Chae, Jong Hee; Choi, Murim

doi:10.1002/ana.25032

Cited by 66 publications

(93 citation statements)

References 59 publications

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“…Stars indicate approximate locations of the eight variants identified in the present study. Circles indicate previously published missense (dark blue) and in‐frame deletion (pink) variants, and truncating variants are indicated by triangles: nonsense (red), frameshift (light blue), and splice‐site (orange) . Variant positions are based on the previously published LeuT crystal structure .…”

Section: Resultsmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [ H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

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Section: Resultsmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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“…Mouse Kctd8, Kctd12, Kctd12b (not found in humans), and Kctd16 belong to clade F of the KCTD protein family (Figure , Table ) and are considered auxiliary subunits of the inhibitory neurotransmitter receptor complex GABA B1/2 (G‐protein‐coupled receptor/GPCR 3 family) present on both inhibitory and excitatory neurons . Supported by studies in GABA B ‐deficient mice, GABA B receptor aberrations are implicated in neurodegenerative and neuropsychiatric disorders, including seizure disorders, depression, schizophrenia, addiction, and several neurodevelopmental disorders . Therefore, disruption of the auxiliary subunits KCTD8, KCTD12, and KCTD16 may cause related conditions.…”

Section: Kctd Genes Associated With Neurodevelopmental and Neuropsychmentioning

confidence: 99%

“…17,59 Supported by studies in GABA B -deficient mice, GABA B receptor aberrations are implicated in neurodegenerative and neuropsychiatric disorders, including seizure disorders, depression, schizophrenia, addiction, and several neurodevelopmental disorders. [59][60][61] Therefore, disruption of the auxiliary subunits KCTD8, KCTD12, and KCTD16 may cause related conditions. A mutation in the promoter region of human KCTD12 was reported to contribute to bipolar I disorder.…”

Section: Kctd8 Kctd12 and Kctd16 In Neurotransmitter Receptor Sigmentioning

confidence: 99%

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

et al. 2019

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The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well‐characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders ( KCTD3 ), neurodevelopmental disease ( KCTD7 ), bipolar disorder ( KCTD12 ), autism and schizophrenia ( KCTD13 ), movement disorders ( KCTD17 ), cancer ( KCTD11 ), and obesity ( KCTD15 ). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD‐related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy‐lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure‐based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.

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“…ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca++, calcium; H+, hydrogen ion; K+, potassium; Na+, sodium; GDP, guanosine diphosphate; Glu, glucose; GTP, guanosine triphosphate; P, phosphate; RBC, red blood cell; a, b, c, alpha, beta, and gamma subunits of guanine nucleotide-binding proteins (G proteins). Finally, mutations in GABRB2, recently identified in DEE, 56 also cause a 'MECP2-like' clinical phenotype 57 consisting of neurological regression with developmental plateauing, hand stereotypies, autonomic dysfunction, sleep disturbance, microcephaly, and GTCS. 50 Recently a de novo GABRA2 mutation was found in a patient with DEE, who also had severe hypotonia, and continuous choreiform movements.…”

Section: Sodium Channel Genesmentioning

confidence: 99%

“…[Colour figure can be viewed at wileyonlinelibrary.com] extrapyramidal features include myoclonus, dystonia, choreoathetosis, hand stereotypies, and bruxism. 57 Related to GABA type A function, ARHGEF9 encodes a protein crucial for the formation of gephyrin and gephyrin-dependent GABA type A clusters in the postsynaptic membrane. 51 GABRB3 mutations, previously linked with Angelman syndrome, autism, and absence seizures, have recently been implicated in DEE such as West syndrome and later onset epilepsy syndromes such as LGS and myoclonic atonic epilepsy.…”

Section: Sodium Channel Genesmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy

Abstract: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.

Cited by 66 publications

References 59 publications

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

The expanding spectrum of movement disorders in genetic epilepsies

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