Disruption of the ATXN1–CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans

Abstract

Gain-of function mutations in some genes underlie neurodegenerative conditions whereas loss-of-function mutations have distinct phenotypes. Such appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain-of-function of the complex leads to neurodegeneration, but ATXIN1-CIC is also essential for survival. We set out to understand the functions of ATXN1-CIC in the developing forebrain and found that losing the complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper layer cortical neurons. We also found that CIC modulates social interactions in the hypothalamus and medial amygdala. Informed by these neurobehavioral features in mouse mutants, we identified five patients with de novo heterozygous truncating mutations in CIC that share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

A double‐edged sword: The world according to Capicua in cancer

“…Interaction between CIC and ATXN1 protein family is also important for brain development. Disruption of the ATXN1/CIC complex affects thickness of cerebral cortex, inducing multiple behavioral abnormalities in mice . In human, the germline heterozygous CIC truncating mutations were reported in patients of intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorder .…”

“…Disruption of the ATXN1/CIC complex affects thickness of cerebral cortex, inducing multiple behavioral abnormalities in mice . In human, the germline heterozygous CIC truncating mutations were reported in patients of intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorder . The Cic‐L knockout homozygous mutant also shows downregulation of transporter genes such as Bsep and Mdr2 in hepatocytes showing bile acid accumulation .…”

“…(26) In human, the germline heterozygous CIC truncating mutations were reported in patients of intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorder. (26) The Cic-L knockout homozygous mutant also shows downregulation of transporter genes such as Bsep and Mdr2 in hepatocytes showing bile acid accumulation. (27) CIC is ubiquitously expressed in many organs except for kidney, and thus its function is important for homeostasis of multiple organs.…”

Building dialogues between clinical and biomedical research through cross-species collaborations

“…This strategy is key to the discovery or co-discovery of the genetic basis of many disorders and understanding the mechanisms of disease. Frequent interactions and collaborations between clinical medicine and biomedical research at the NRI fostered our understanding of several diseases including Fragile X syndrome, Angelman syndrome, Rett syndrome, MECP2 duplication syndrome, myotonic dystrophy, Parkinson’s disease, Alzheimer’s disease, Spinocerebellar ataxia type 1, Friederich’s ataxia, amyotrophic lateral sclerosis, Leigh syndrome, Charcot-Marie-Tooth, other inherited ataxias, neuropathies, lysosomal storage disorders, epilepsies, and syndromic neurodevelopmental disorders [21, 28, 35–42]. …”

Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

“…In mammals, CIC has been implicated in the pathogenesis of spinocerebellar ataxia type 1 neurodegenerative disease, as well as regulation of essential processes such as lung alveolarization, liver homeostasis, learning and memory, and follicular helper T‐cell differentiation . CIC has also been studied in several cancer contexts, and mutations of it have been found in soft tissue, brain, lung, gastric, prostate, and breast cancers .…”