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Willim, J.* ; Woike, D.* ; Greene, D.* ; Das, S.* ; Pfeifer, K.* ; Yuan, W.* ; Lindsey, A.* ; Itani, O.* ; Böhme, A.L.* ; Tibbe, D.* ; Hönck, H.H.* ; Hassani Nia, F.* ; Zech, M. ; Brunet, T. ; Faivre, L.* ; Sorlin, A.* ; Vitobello, A.* ; Smol, T.* ; Colson, C.* ; Baranano, K.* ; Schatz, K.* ; Bayat, A.* ; Schoch, K.* ; Spillmann, R.C.* ; Davis, E.E.* ; Conboy, E.* ; Vetrini, F.* ; Platzer, K.* ; Neuser, S.* ; Gburek-Augustat, J.* ; Grace, A.N.* ; Mitchell, B.D.* ; Stegmann, A.P.* ; Sinnema, M.* ; Meeks, N.* ; Saunders, C.* ; Cadieux-Dion, M.* ; Hoyer, J.* ; Van-Gils, J.* ; de Sainte-Agathe, J.M.* ; Thompson, M.L.* ; Bebin, E.M.* ; Weisz-Hubshman, M.* ; Tabet, A.C.* ; Verloes, A.* ; Lévy, J.* ; Latypova, X.* ; Harder, S.* ; Silverman, G.A.* ; Pak, S.C.* ; Schedl, T.* ; Freson, K.* ; Mumford, A.* ; Turro, E.* ; Schlein, C.* ; Shashi, V.* ; Kreienkamp, H.J.*

Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors.

Nat. Commun. 15:7909 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Protein-kinase-ii; Repeat Protein; Association; Densin-180; Deletion; Subunit; Complex; Shank3; Identification; Spinophilin
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 7909 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERNE-ITHACA
Deutsche Forschungsgemeinschaft
Medical Research Council
Cancer Research UK
Wellcome Trust
NHS England
National Institute for Health Research
Jung-Stiftung fur Wissenschaft und Forschung
Else Kroner-Fresenius-Stiftung
Technical University of Munich-Institute for Advanced Study
Free State of Bavaria under the Excellence Strategy of the Federal Government
Federal Ministry of Education and Research (BMBF)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
NIH CommonFund, through the Office of StrategicCoordination/Office of theNIH Director
Deutsche Forschungsgemeinschaft (DFG)