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

Jana Willim, Daniel Woike, Daniel Greene, Sarada Das, Kevin Pfeifer, Weimin Yuan, Anika Lindsey, Omar Itani, Amber L. Böhme, Debora Tibbe, Hans-Hinrich Hönck, Fatemeh Hassani Nia, Michael Zech, Theresa Brunet, Laurence Faivre, Arthur Sorlin, Antonio Vitobello, Thomas Smol, Cindy Colson, Kristin Baranano, Krista Schatz, Allan Bayat, Kelly Schoch, Rebecca Spillmann, Erica E. Davis, Erin Conboy, Francesco Vetrini, Konrad Platzer, Sonja Neuser, Janina Gburek-Augustat, Alexandra Noel Grace, Bailey Mitchell, Alexander Stegmann, Margje Sinnema, Naomi Meeks, Carol Saunders, Maxime Cadieux-Dion, Juliane Hoyer, Julien Van-Gils, Jean-Madeleine Sainte-Agathe, Michelle L. Thompson, E. Martina Bebin, Monika Weisz-Hubshman, Anne-Claude Tabet, Alain Verloes, Jonathan Levy, Xenia Latypova, Sönke Harder, Gary A. Silverman, Stephen C. Pak, Tim Schedl, Kathleen Freson, Andrew Mumford, Ernest Turro, Christian Schlein, Vandana Shashi and Hans-Jürgen Kreienkamp ()
Additional contact information
Jana Willim: University Medical Center Hamburg-Eppendorf
Daniel Woike: University Medical Center Hamburg-Eppendorf
Daniel Greene: Icahn School of Medicine at Mount Sinai
Sarada Das: University Medical Center Hamburg-Eppendorf
Kevin Pfeifer: University Medical Center Hamburg-Eppendorf
Weimin Yuan: Washington University in St Louis School of Medicine
Anika Lindsey: Washington University in St Louis School of Medicine
Omar Itani: Washington University in St Louis School of Medicine
Amber L. Böhme: University Medical Center Hamburg-Eppendorf
Debora Tibbe: University Medical Center Hamburg-Eppendorf
Hans-Hinrich Hönck: University Medical Center Hamburg-Eppendorf
Fatemeh Hassani Nia: University Medical Center Hamburg-Eppendorf
Michael Zech: Technical University of Munich
Theresa Brunet: Technical University of Munich
Laurence Faivre: CHU Dijon-Bourgogne
Arthur Sorlin: INSERM—Université de Bourgogne—UMR1231 GAD
Antonio Vitobello: INSERM—Université de Bourgogne—UMR1231 GAD
Thomas Smol: Univ. Lille, CHU Lille, ULR7364 – RADEME
Cindy Colson: Univ. Lille, CHU Lille, ULR7364 – RADEME
Kristin Baranano: Johns Hopkins University School of Medicine
Krista Schatz: Johns Hopkins University School of Medicine
Allan Bayat: Danish Epilepsy Center
Kelly Schoch: Duke University School of Medicine
Rebecca Spillmann: Duke University School of Medicine
Erica E. Davis: Duke University Medical Center
Erin Conboy: Indiana University School of Medicine
Francesco Vetrini: Indiana University School of Medicine
Konrad Platzer: University of Leipzig Medical Center
Sonja Neuser: University of Leipzig Medical Center
Janina Gburek-Augustat: University of Leipzig Medical Center
Alexandra Noel Grace: Baylor College of Medicine
Bailey Mitchell: Baylor College of Medicine in San Antonio
Alexander Stegmann: Maastricht University Medical Center
Margje Sinnema: Maastricht University Medical Center
Naomi Meeks: Division of Clinical Genetics & Metabolism
Carol Saunders: Children’s Mercy Hospital
Maxime Cadieux-Dion: Children’s Mercy Hospital
Juliane Hoyer: Friedrich-Alexander-Universität Erlangen-Nürnberg
Julien Van-Gils: Centre Hospitalier Universitaire (CHU) de Bordeaux
Jean-Madeleine Sainte-Agathe: Centre Hospitalier Universitaire (CHU) de Bordeaux
Michelle L. Thompson: HudsonAlpha Institute for Biotechnology
E. Martina Bebin: University of Alabama at Birmingham
Monika Weisz-Hubshman: Baylor College of Medicine
Anne-Claude Tabet: APHP-Robert Debré University Hospital
Alain Verloes: APHP-Robert Debré University Hospital
Jonathan Levy: APHP-Robert Debré University Hospital
Xenia Latypova: APHP-Robert Debré University Hospital
Sönke Harder: University Medical Center Hamburg-Eppendorf
Gary A. Silverman: Washington University in St Louis School of Medicine
Stephen C. Pak: Washington University in St Louis School of Medicine
Tim Schedl: Washington University in St Louis School of Medicine
Kathleen Freson: KU Leuven
Andrew Mumford: University of Bristol
Ernest Turro: Icahn School of Medicine at Mount Sinai
Christian Schlein: University Medical Center Hamburg-Eppendorf
Vandana Shashi: Duke University School of Medicine
Hans-Jürgen Kreienkamp: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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 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.

Date: 2024
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DOI: 10.1038/s41467-024-52095-x

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