Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2.
Three brothers with autism share the same rare stop mutation in the stress-related NR3C2 gene.
01Research in Context
What this study did
Doctors sequenced the DNA of three brothers who all have autism. They found the same rare mutation in every boy. The mutation stops the NR3C2 gene from making its full protein. NR3C2 helps control the stress hormone aldosterone.
What they found
All three brothers share a 'stop-gain' glitch in NR3C2. This change tells the cell to quit building the protein halfway. The mineralocorticoid receptor that NR3C2 makes is missing its tail. No other family members carried the mutation.
How this fits with other research
Almatrafi et al. (2023) also looked at brothers with autism and found a different metabolic mutation. Both papers show that rare single-gene changes can travel in brothers. Sakurai et al. (2008) screened 1200 people and saw no autism link to the serotonin transporter gene. Their big sample says that gene is not a major player, while Hand et al. (2020) show NR3C2 might be. Boswell et al. (2023) pooled 25 studies and found no useful blood markers for autism. Their null result keeps the door open for genetic markers like NR3C2 instead.
Why it matters
If you assess a family with more than one child with autism, consider referral for whole-exome sequencing. A shared rare mutation gives families a clear genetic answer and helps you plan supports around stress-response issues linked to the mineralocorticoid pathway.
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02At a glance
03Original abstract
Whole exome sequencing and copy-number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop-gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone-regulated transcription factor that acts in the hypothalamic-pituitary-adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523-531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.
Autism research : official journal of the International Society for Autism Research, 2020 · doi:10.1002/aur.2269