Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Nuclear receptor 2E1 (NR2E1) is present in human brains, but its function in brain-behavior development is unclear.
• Previous studies in mice suggest NR2E1's role in cortical development and behavior.

Purpose of the Study:

• To investigate the role of NR2E1 mutations in human brain-behavior development disorders, specifically microcephaly.
• To screen for NR2E1 mutations in patients with cortical disorders and analyze their potential impact.

Main Methods:

• Sequenced the entire coding region, untranslated regions, splice sites, promoter, and conserved non-coding regions of NR2E1 in 56 patients with microcephaly.
• Genotyped candidate mutations in 325 controls and 15 relatives.
• Utilized in silico tools to predict the impact of mutations on neural transcription factor binding sites (TFBS).
• Analyzed NR2E1 molecular evolution, genetic diversity, and haplotype structure in a global human population and non-human primates.

Main Results:

• No coding region mutations in NR2E1 were found in patients.
• Seven novel candidate regulatory mutations were identified in patients and absent in controls.
• Four candidate mutations were predicted to affect TFBS.
• NR2E1 exhibits strong purifying selection, low genetic diversity, 21 novel polymorphisms, and five common haplotypes.

Conclusions:

• Protein-coding mutations in NR2E1 are not a cause of the examined cortical and behavioral abnormalities.
• Regulatory mutations in NR2E1 may play a role in human brain-behavior development disorders.