TY - JOUR
T1 - Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors
AU - Willim, Jana
AU - Woike, Daniel
AU - Greene, Daniel
AU - Das, Sarada
AU - Pfeifer, Kevin
AU - Yuan, Weimin
AU - Lindsey, Anika
AU - Itani, Omar
AU - Böhme, Amber L.
AU - Tibbe, Debora
AU - Hönck, Hans Hinrich
AU - Hassani Nia, Fatemeh
AU - Zech, Michael
AU - Brunet, Theresa
AU - Faivre, Laurence
AU - Sorlin, Arthur
AU - Vitobello, Antonio
AU - Smol, Thomas
AU - Colson, Cindy
AU - Baranano, Kristin
AU - Schatz, Krista
AU - Bayat, Allan
AU - Schoch, Kelly
AU - Spillmann, Rebecca
AU - Davis, Erica E.
AU - Conboy, Erin
AU - Vetrini, Francesco
AU - Platzer, Konrad
AU - Neuser, Sonja
AU - Gburek-Augustat, Janina
AU - Grace, Alexandra Noel
AU - Mitchell, Bailey
AU - Stegmann, Alexander
AU - Sinnema, Margje
AU - Meeks, Naomi
AU - Saunders, Carol
AU - Cadieux-Dion, Maxime
AU - Hoyer, Juliane
AU - Van-Gils, Julien
AU - de Sainte-Agathe, Jean Madeleine
AU - Thompson, Michelle L.
AU - Bebin, E. Martina
AU - Weisz-Hubshman, Monika
AU - Tabet, Anne Claude
AU - Verloes, Alain
AU - Levy, Jonathan
AU - Latypova, Xenia
AU - Harder, Sönke
AU - Silverman, Gary A.
AU - Pak, Stephen C.
AU - Schedl, Tim
AU - Freson, Kathleen
AU - Mumford, Andrew
AU - Turro, Ernest
AU - Schlein, Christian
AU - Shashi, Vandana
AU - Kreienkamp, Hans-Jürgen
AU - Undiagnosed Diseases Network
N1 - Publisher Copyright:
© 2024. The Author(s).
PY - 2024/9/10
Y1 - 2024/9/10
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aggression
KW - Animals
KW - Autistic Disorder/genetics
KW - Child
KW - Child, Preschool
KW - Female
KW - HEK293 Cells
KW - Humans
KW - Intellectual Disability/genetics
KW - Male
KW - Membrane Proteins/genetics
KW - Nerve Tissue Proteins/genetics
KW - Neurons/metabolism
KW - PDZ Domains/genetics
KW - Synapses/metabolism
KW - Young Adult
U2 - 10.1038/s41467-024-52095-x
DO - 10.1038/s41467-024-52095-x
M3 - Journal article
C2 - 39256359
AN - SCOPUS:85203981136
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
M1 - 7909
ER -