Document Type

Article

Publication Date

9-10-2024

Identifier

DOI: 10.1038/s41467-024-52095-x; PMCID: PMC11387733

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.

Journal Title

Nat Commun

Volume

15

Issue

1

First Page

7909

Last Page

7909

MeSH Keywords

Humans; Intellectual Disability; Autistic Disorder; Aggression; Male; Female; Child; HEK293 Cells; Neurons; Adolescent; Membrane Proteins; Adult; Animals; Child, Preschool; Nerve Tissue Proteins; Young Adult; Synapses; PDZ Domains

Keywords

Intellectual Disability; Autistic Disorder; Aggression; HEK293 Cells; Neurons; Membrane Proteins; Animals; Nerve Tissue Proteins; Synapses; PDZ Domains

Comments

Grants and funding

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Link: https://www.nature.com/articles/s41467-024-52095-x

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