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  1. Article ; Online: Schip1, a new upstream regulator of Hippo signaling.

    Chung, Hyung-Lok / Choi, Kwang-Wook

    Cell cycle (Georgetown, Tex.)

    2016  Volume 15, Issue 16, Page(s) 2097–2098

    MeSH term(s) Animals ; Drosophila Proteins ; Drosophila melanogaster ; Intracellular Signaling Peptides and Proteins ; Protein-Serine-Threonine Kinases ; Signal Transduction
    Chemical Substances Drosophila Proteins ; Intracellular Signaling Peptides and Proteins ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; hpo protein, Drosophila (EC 2.7.11.1)
    Language English
    Publishing date 2016-05-31
    Publishing country United States
    Document type Editorial
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.1080/15384101.2016.1191252
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    Zs.A 5881: Show issues Location:
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  2. Article ; Online: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.

    Liao, Jenny Zhe / Chung, Hyung-Lok / Shih, Claire / Wong, Kenneth Kin Lam / Dutta, Debdeep / Nil, Zelha / Burns, Catherine Grace / Kanca, Oguz / Park, Ye-Jin / Zuo, Zhongyuan / Marcogliese, Paul C / Sew, Katherine / Bellen, Hugo J / Verheyen, Esther M

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 3326

    Abstract: Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. ... ...

    Abstract Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. We show that Cdk8 promotes the phosphorylation of Drp1 at S616, a protein required for mitochondrial fission. Interestingly, Pink1, a mitochondrial kinase implicated in Parkinson's disease, also phosphorylates Drp1 at the same residue. Indeed, overexpression of Cdk8 significantly suppresses the phenotypes observed in flies with low levels of Pink1, including elevated levels of ROS, mitochondrial dysmorphology, and behavioral defects. In summary, we propose that Pink1 and Cdk8 perform similar functions to promote Drp1-mediated fission.
    MeSH term(s) Animals ; Humans ; Phosphorylation ; Drosophila/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Mitochondrial Dynamics/genetics ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Cyclin-Dependent Kinase 8/genetics ; Cyclin-Dependent Kinase 8/metabolism
    Chemical Substances Drosophila Proteins ; CDK19 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Cdk8 protein, Drosophila (EC 2.7.11.22) ; Cyclin-Dependent Kinase 8 (EC 2.7.11.22)
    Language English
    Publishing date 2024-04-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-47623-8
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  3. Article ; Online: Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation.

    Chung, Hyung-Lok / Ye, Qi / Park, Ye-Jin / Zuo, Zhongyuan / Mok, Jung-Wan / Kanca, Oguz / Tattikota, Sudhir Gopal / Lu, Shenzhao / Perrimon, Nobert / Lee, Hyun Kyoung / Bellen, Hugo J

    Cell metabolism

    2023  Volume 35, Issue 5, Page(s) 855–874.e5

    Abstract: VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via ...

    Abstract VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also toxic in vertebrates based on a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Indeed, reducing VLCFA with bezafibrate ameliorates the phenotypes. Moreover, simultaneous use of bezafibrate and fingolimod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a treatment avenue for MS.
    MeSH term(s) Mice ; Animals ; Fingolimod Hydrochloride/pharmacology ; Fingolimod Hydrochloride/therapeutic use ; Immunosuppressive Agents/pharmacology ; Neuroinflammatory Diseases ; Bezafibrate ; Propylene Glycols/pharmacology ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Multiple Sclerosis ; Neuroglia/metabolism ; Fatty Acids
    Chemical Substances Fingolimod Hydrochloride (G926EC510T) ; sphingosine 1-phosphate (26993-30-6) ; Immunosuppressive Agents ; Bezafibrate (Y9449Q51XH) ; Propylene Glycols ; Fatty Acids
    Language English
    Publishing date 2023-04-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2023.03.022
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  4. Article ; Online: Drosophila Schip1 Links Expanded and Tao-1 to Regulate Hippo Signaling.

    Chung, Hyung-Lok / Augustine, George J / Choi, Kwang-Wook

    Developmental cell

    2016  Volume 36, Issue 5, Page(s) 511–524

    Abstract: Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors ...

    Abstract Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors by inhibiting Yorkie (Yki). Expanded (Ex) is a regulator of the Hpo activity, but how they are linked is unknown. Here, we show that Schip1, a Drosophila homolog of the mammalian Schwannomin interacting protein 1 (SCHIP1), provides a link between Ex and Hpo. Ex is required for apical localization of Schip1 in imaginal discs. Schip1 is necessary for promoting membrane localization and phosphorylation of Hpo by recruiting the Hpo kinase Tao-1. Taking these findings together, we conclude that Schip1 directly links Ex to Hpo signaling by recruiting Tao-1. This study provides insights into the mechanism of Tao-1 regulation and a potential growth control function for SCHIP1 in mammals.
    MeSH term(s) Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Polarity/physiology ; Cell Proliferation/physiology ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Kinase Kinases/genetics ; MAP Kinase Kinase Kinases/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction/genetics ; Trans-Activators/metabolism
    Chemical Substances Carrier Proteins ; Drosophila Proteins ; Intracellular Signaling Peptides and Proteins ; Schwannomin interacting protein 1, Drosophila ; Trans-Activators ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; TAO1 protein kinase (EC 2.7.11.1) ; hpo protein, Drosophila (EC 2.7.11.1) ; MAP Kinase Kinase Kinases (EC 2.7.11.25)
    Language English
    Publishing date 2016-03-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2016.02.004
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  5. Article ; Online: The fly homolog of SUPT16H, a gene associated with neurodevelopmental disorders, is required in a cell-autonomous fashion for cell survival.

    Ma, Mengqi / Zhang, Xi / Zheng, Yiming / Lu, Shenzhao / Pan, Xueyang / Mao, Xiao / Pan, Hongling / Chung, Hyung-Lok / Wang, Hua / Guo, Hong / Bellen, Hugo J

    Human molecular genetics

    2022  Volume 32, Issue 6, Page(s) 984–997

    Abstract: SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in ... ...

    Abstract SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in SUPT16H. The probands exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and brain structural abnormalities. We used Drosophila to characterize two variants: p.T171I and p.G808R. Loss of the fly ortholog, dre4, causes lethality at an early developmental stage. RNAi-mediated knockdown of dre4 in either glia or neurons causes severely reduced eclosion and longevity. Tissue-specific knockdown of dre4 in the eye or wing leads to the loss of these tissues, whereas overexpression of SUPT16H has no dominant effect. Moreover, expression of the reference SUPT16H significantly rescues the loss-of-function phenotypes in the nervous system as well as wing and eye. In contrast, expression of SUPT16H p.T171I or p.G808R rescues the phenotypes poorly, indicating that the variants are partial loss-of-function alleles. While previous studies argued that the developmental arrest caused by loss of dre4 is due to impaired ecdysone production in the prothoracic gland, our data show that dre4 is required for proper cell growth and survival in multiple tissues in a cell-autonomous manner. Altogether, our data indicate that the de novo loss-of-function variants in SUPT16H are indeed associated with developmental and neurological defects observed in the probands.
    MeSH term(s) Animals ; Cell Survival ; Neurodevelopmental Disorders/genetics ; Intellectual Disability/genetics ; Epilepsy ; Mutation, Missense ; Brain Diseases ; Drosophila
    Language English
    Publishing date 2022-10-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddac259
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    Zs.A 3469: Show issues Location:
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  6. Article ; Online: De novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila.

    Chung, Hyung-Lok / Rump, Patrick / Lu, Di / Glassford, Megan R / Mok, Jung-Wan / Fatih, Jawid / Basal, Adily / Marcogliese, Paul C / Kanca, Oguz / Rapp, Michele / Fock, Johanna M / Kamsteeg, Erik-Jan / Lupski, James R / Larson, Austin / Haninbal, Mark C / Bellen, Hugo / Harel, Tamar

    Human molecular genetics

    2022  Volume 31, Issue 19, Page(s) 3231–3244

    Abstract: Background: The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar ... ...

    Abstract Background: The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse.
    Methods: Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the dysfunction was specific to one cell type.
    Results: Exome sequencing identified de novo variants in EMC1 in three individuals affected by global developmental delay, hypotonia, seizures, visual impairment and cerebellar atrophy. All variants were located at Pro582 or Pro584. Drosophila studies indicated that imbalance of EMC1-either overexpression or knockdown-results in pupal lethality and suggest that the tested homologous variants are LoF alleles. In addition, glia-specific gene dosage, overexpression or knockdown, of EMC1 led to lethality, whereas neuron-specific alterations were tolerated.
    Discussion: We establish de novo monoallelic EMC1 variants as causative of a neurological disease trait by providing functional evidence in a Drosophila model. The identified variants failed to rescue the lethality of a null allele. Variations in dosage of the wild-type EMC1, specifically in glia, lead to pupal lethality, which we hypothesize results from the altered stoichiometry of the multi-subunit protein complex EMC.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cerebellar Diseases/genetics ; Drosophila/genetics ; Drosophila Proteins/genetics ; Intellectual Disability ; Membrane Proteins/genetics ; Nervous System Malformations ; Neurodegenerative Diseases ; Neurodevelopmental Disorders/genetics ; Neuroglia ; Repressor Proteins
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Drosophila Proteins ; Membrane Proteins ; Repressor Proteins ; emc protein, Drosophila
    Language English
    Publishing date 2022-03-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddac053
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  7. Article ; Online: Phosphatidylserine synthase plays an essential role in glia and affects development, as well as the maintenance of neuronal function.

    Park, Ye-Jin / Kim, Sungkyung / Shim, Hyeon-Pyo / Park, Jae H / Lee, Gyunghee / Kim, Tae-Yeop / Jo, Min-Cue / Kwon, Ah-Young / Lee, Mihwa / Lee, Seongjae / Yeo, Jiwon / Chung, Hyung-Lok / Bellen, Hugo J / Kwon, Seung-Hae / Jeon, Sang-Hak

    iScience

    2021  Volume 24, Issue 8, Page(s) 102899

    Abstract: Phosphatidylserine (PS) is an integral component of eukaryotic cell membranes and organelles. ... ...

    Abstract Phosphatidylserine (PS) is an integral component of eukaryotic cell membranes and organelles. The
    Language English
    Publishing date 2021-07-24
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2021.102899
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  8. Article ; Online: Phosphatidylserine synthase plays an essential role in glia and affects development, as well as the maintenance of neuronal function

    Ye-Jin Park / Sungkyung Kim / Hyeon-Pyo Shim / Jae H. Park / Gyunghee Lee / Tae-Yeop Kim / Min-Cue Jo / Ah-Young Kwon / Mihwa Lee / Seongjae Lee / Jiwon Yeo / Hyung-Lok Chung / Hugo J. Bellen / Seung-Hae Kwon / Sang-Hak Jeon

    iScience, Vol 24, Iss 8, Pp 102899- (2021)

    2021  

    Abstract: Summary: Phosphatidylserine (PS) is an integral component of eukaryotic cell membranes and organelles. The Drosophila genome contains a single PS synthase (PSS)-encoding gene (Pss) homologous to mammalian PSSs. Flies with Pss loss-of-function alleles ... ...

    Abstract Summary: Phosphatidylserine (PS) is an integral component of eukaryotic cell membranes and organelles. The Drosophila genome contains a single PS synthase (PSS)-encoding gene (Pss) homologous to mammalian PSSs. Flies with Pss loss-of-function alleles show a reduced life span, increased bang sensitivity, locomotor defects, and vacuolated brain, which are the signs associated with neurodegeneration. We observed defective mitochondria in mutant adult brain, as well as elevated production of reactive oxygen species, and an increase in autophagy and apoptotic cell death. Intriguingly, glial-specific knockdown or overexpression of Pss alters synaptogenesis and axonal growth in the larval stage, causes developmental arrest in pupal stages, and neurodegeneration in adults. This is not observed with pan-neuronal up- or down-regulation. These findings suggest that precisely regulated expression of Pss in glia is essential for the development and maintenance of brain function. We propose a mechanism that underlies these neurodegenerative phenotypes triggered by defective PS metabolism.
    Keywords Developmental neuroscience ; Cell biology ; Developmental biology ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
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  9. Article ; Online: Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures.

    Lu, Shenzhao / Hernan, Rebecca / Marcogliese, Paul C / Huang, Yan / Gertler, Tracy S / Akcaboy, Meltem / Liu, Shiyong / Chung, Hyung-Lok / Pan, Xueyang / Sun, Xiaoqin / Oguz, Melahat Melek / Oztoprak, Ulkühan / de Baaij, Jeroen H F / Ivanisevic, Jelena / McGinnis, Erin / Guillen Sacoto, Maria J / Chung, Wendy K / Bellen, Hugo J

    American journal of human genetics

    2022  Volume 109, Issue 4, Page(s) 571–586

    Abstract: TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. ... ...

    Abstract TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.
    MeSH term(s) Alleles ; Animals ; Child ; DNA, Complementary ; Developmental Disabilities/genetics ; Developmental Disabilities/pathology ; Drosophila/genetics ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/pathology ; Phenotype ; Seizures/genetics ; T-Lymphoma Invasion and Metastasis-inducing Protein 1/genetics
    Chemical Substances DNA, Complementary ; T-Lymphoma Invasion and Metastasis-inducing Protein 1 ; TIAM1 protein, human
    Language English
    Publishing date 2022-03-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2022.01.020
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  10. Article ; Online: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.

    Manivannan, Sathiya N / Roovers, Jolien / Smal, Noor / Myers, Candace T / Turkdogan, Dilsad / Roelens, Filip / Kanca, Oguz / Chung, Hyung-Lok / Scholz, Tasja / Hermann, Katharina / Bierhals, Tatjana / Caglayan, Hande S / Stamberger, Hannah / Mefford, Heather / de Jonghe, Peter / Yamamoto, Shinya / Weckhuysen, Sarah / Bellen, Hugo J

    Brain : a journal of neurology

    2021  Volume 145, Issue 5, Page(s) 1684–1697

    Abstract: FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients ... ...

    Abstract FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases.
    MeSH term(s) Ataxia ; Cdh1 Proteins/genetics ; Child ; Epilepsy/genetics ; Epilepsy, Generalized/genetics ; Humans ; Loss of Function Mutation ; Microcephaly/genetics ; Phenotype
    Chemical Substances Cdh1 Proteins ; FZR1 protein, human
    Language English
    Publishing date 2021-11-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab409
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