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.

富含亮氨酸重复序列 (LRR) 和 PDZ 结构域 (LAP) 蛋白家族的成员对于动物发育和组织发生至关重要。 Densin-180 由LRRC7编码，是唯一在神经元中选择性表达的 LAP 蛋白。 Densin-180 是谷氨酸能突触的突触后支架，将细胞骨架元件与信号蛋白（例如 Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II 的 α 亚基）连接起来。我们之前观察到LRRC7的高影响变异与智力障碍之间存在关联；还描述了LRRC7变异的三个个案。我们在此鉴定出 33 名个体（其中一位之前已描述过）由于LRRC7杂合错义或功能缺失变异而患有显性神经发育障碍。临床范围包括智力障碍、自闭症、注意力缺陷多动症、攻击性，在某些情况下，还包括与暴食相关的肥胖。 PDZ 结构域变体会干扰原代培养神经元中 Densin-180 的突触靶向。使用体外系统（来自 293T 细胞的两个混合、BioID、标记蛋白的免疫共沉淀），我们鉴定了 LRR 结构域的新候选相互作用伙伴，包括蛋白磷酸酶 1 (PP1)，并观察到 ​​LRR 中的变体减少了与这些蛋白的结合。我们得出的结论是， LRRC7编码了智力发展和行为的主要决定因素。