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

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 Ca<sup>2+</sup>/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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Publication Details

Journal
Nature Communications
Published
2024-09-10
DOI
https://doi.org/10.1038/s41467-024-52095-x
Citations
7
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
3.85

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article

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

Michelle L. Thompson, Alain Verloès, Krista Schatz, Christian Schlein et al.
7 citations
Nature Communications
Genetics and Neurodevelopmental Disorders
3.85
article

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

Michelle L. Thompson, Alain Verloès, Krista Schatz, Christian Schlein, Fatemeh Hassani Nia, Michael Zech, Konrad Platzer, Erica E. Davis, Kristin Barañano, Theresa Brunet, Ernest Turro, Julien Van‐Gils, Sönke Harder, Jonathan Lévy, Debora Tibbe, Anika Lindsey, Omar A. Itani, Margje Sinnema, Laurence Olivier Faivre, Andrew Mumford, Juliane Hoyer, Francesco Vetrini, Sonja Neuser, Kevin Pfeifer, Tim Schedl, Kelly Schoch, Gary A. Silverman, Cindy Colson, Anne‐Claude Tabet, Hans‐Hinrich Hönck, Daniel Woike, Stephen C. Pak, Erin Conboy, Janina Gburek‐Augustat, Alexandra N Grace, Xénia Latypova, Antonio Vitobello, Hans‐Jürgen Kreienkamp, Kathleen Freson, Arthur Sorlin, Allan Bayat, Alexander P.A. Stegmann, Naomi Meeks, Thomas Smol, Carol Saunders, Daniel Greene, Sarada Das, Vandana Shashi, Maxime Cadieux‐Dion, Jean-Madeleine de Sainte-Agathe, E. Martina Bebin, Weimin Yuan, Jana Willim, Rebecca C. Spillmann, Amber L Böhme, Bailey W. Mitchell, Monika Weisz‐Hubshman
article en
7 citations

Abstract

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 Ca<sup>2+</sup>/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.

Nature CommunicationsVol. 15(1)
Northwestern University (US), University of Copenhagen (DK), Lurie Children's Hospital (US), Children's Mercy Hospital (US), Johns Hopkins University (US), Inserm (FR), Universität Hamburg (DE), Duke University (US), Université de Bourgogne (FR), University of Southern Denmark (DK), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Baylor College of Medicine (US), Washington University in St. Louis (US), Université de Lille (FR), Johns Hopkins Medicine (US), Helmholtz Zentrum München (DE), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), University of Alabama at Birmingham (US), Maastricht University (NL), University of Bristol (GB), Children's Hospital Colorado (US), Assistance Publique – Hôpitaux de Paris (FR), University Medical Center Hamburg-Eppendorf (DE), CHU Dijon Bourgogne (FR), University Hospital Leipzig (DE), Duke Medical Center (US), Hôpital Robert-Debré (FR), Institute for Advanced Study (DE), HudsonAlpha Institute for Biotechnology (US), Texas Children's Hospital (US), Mercy Research (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Technical University of Munich (DE), University of Missouri–Kansas City (US), University of Colorado Denver (US), Leipzig University (DE), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
Wellcome Trust, Australian Government, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius-Stiftung, Jung-Stiftung für Wissenschaft und Forschung, Technische Universität München, National Institutes of Health, Medical Research Council, Common Fund
Openalex Percentile: Top 6%
Genetics and Neurodevelopmental Disorders
3.85
DOIOpen Access PDFOpenAlex
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