NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder

Abstract

NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.

Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment

“…To our knowledge, this is the first time a point mutation leading to loss of function in NR4A2 is reported. Our patient's phenotype is similar to the previously described in individuals with de novo microdeletions encompassing NR4A2 at the 2q24.1 region and whose clinical manifestations were mainly characterized by language and cognitive delay . Our patient also presented focal motor seizures in the rolandic epilepsy spectrum, which expands the clinical manifestations related to NR4A2 haploinsufficiency and reinforces the predominance of language impairment associated with this condition.…”

“…NR4A2 haploinsufficiency due to whole gene deletion was recently associated with neurodevelopmental and language delay phenotypes by Reuter et al and Lévy et al This finding strongly suggests that NR4A2 is the critical gene for 2q24.1 microdeletion syndrome.…”

Loss‐of‐Function Mutations in NR4A2 Cause Dopa‐Responsive Dystonia Parkinsonism

“…However, subsequent studies did not replicate the aforementioned finding. Recently, de novo overlapping deletions encompassing NR4A2 were identified in patients with intellectual disability (ID) . Here, we report 2 patients carrying frameshift insertions in NR4A2 resulting in dopa‐responsive dystonia parkinsonism, along with previously reported neurodevelopmental deficit.…”

Working Memory Deficits in Schizophrenia Are Associated With the Rs34884856 Variant and Expression Levels of the NR4A2 Gene in a Sample Mexican Population: A Case Control Study

“…The association of NR4A2 de ciency and reduction in performance on cognitive tasks has been reported for Alzheimer´s disease and attention-de cit hyperactivity disorder animal models [17,20], as well as with reports of its important role in diverse memory tasks in preclinical studies [16,[21][22][23][24]. NR4A2 is also involved in neurodevelopmental disorders and cognitive de cits as reported in clinical trials [14,15].…”

“…This transcription factor regulates the expression of genes involved in the development, survival, and phenotype of dopaminergic neurons [11,12]. The NR4A2 gene (also known as Nurr1) has been related to schizophrenia etiology and cognitive function [9,[13][14][15][16][17]. Notably, in relation to this gene, Nurr1 heterozygous (+/-) mice show cognitive impairment and pharmacological responses consistent with a model for schizophrenia [18,19].…”