What is it about?

R3HDM1 is an uncharacterized RNA-binding protein that is highly expressed in the human cerebral cortex. We report the first case of a patient exhibiting mild intellectual disability and developmental delay with a de novo pericentric inversion disrupting R3HDM1. Knockdown of R3HDM1 in mouse hippocampal neurons suppressed dendritic growth and branching. DGV database reported the case of a healthy control with a deletion that included both R3HDM1 and MIR128-1. miR-128 has been reported to inhibit dendritic growth and branching in mouse brain neurons, which directly opposes the novel functions of R3HDM1. These findings indicate that deleting both R3HDM1 and MIR128-1 alleviates the symptoms of the disease caused by loss of function mutations in only R3HDM1.

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Why is it important?

R3HDM1 is an RNA-binding protein, but the relationship between its function and intellectual disability is still unknown. We report the first case of pericentric inversion disrupting R3HDM1 but does not affect MIR128-1. DGV reported the case of a healthy control with a 488-kb deletion that included both R3HDM1 and MIR128-1. MIR128-1 is deleted in the case of DGV, but is intact in our reported patient. R3HDM1 levels in patients' lymphoblastoid cells were reduced to about half that of healthy controls, while miR128-1 and its mature form, miR-128 expression levels were similar to those in healthy controls. Thus, haploinsufficiency of R3HDM1 in the patient may be the cause of the mild intellectual disability due to the genetic imbalance between R3HDM1 and MIR128-1.


There are few reports that genetic imbalance of a pathogenic candidate gene and microRNA is related to mild intellectual disability. There have been many reports on the determination of etiologic genes for severe intellectual disability, but we hope that this paper will lead to further research on mild intellectual disability.

Daisuke Fukushi

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This page is a summary of: R3HDM1 haploinsufficiency is associated with mild intellectual disability, American Journal of Medical Genetics Part A, March 2021, Wiley,
DOI: 10.1002/ajmg.a.62173.
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