NR2E1 – NR2E1-related Microcephaly

Nuclear receptor NR2E1 (Tlx) is expressed in human fetal and adult brains and is critical for cortical development. In Nr2e1(-/-) mice, cortical hypoplasia and behavioral abnormalities are rescued by a genomic clone containing human NR2E1, supporting its functional importance in brain morphogenesis (PMID:17054721).

In the first comprehensive screen of 56 unrelated patients with severe microcephaly (PMID:17054721), no coding region mutations were identified in NR2E1; however, seven novel non-coding regulatory variants absent from 325 controls were detected, four of which are predicted to disrupt neural transcription factor binding sites. Similarly, in a cohort of five patients with MMEP-related phenotypes including microcephaly, one regulatory variant previously reported in a microcephaly case was found but no coding changes were detected (PMID:17655765).

Despite evidence of strong purifying selection and low genetic diversity at NR2E1, the lack of pathogenic coding variants, absence of segregation data in affected relatives, and the unvalidated impact of regulatory mutations limit the current gene-disease association. Mouse rescue experiments indicate haploinsufficiency as a plausible mechanism, but direct functional validation of human non-coding variants is pending.

Key Take-home: Regulatory variants in NR2E1 are candidate contributors to human microcephaly, but robust segregation and functional studies are required to establish clinical utility.

References

• Genes, brain, and behavior • 2007 • Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations. PMID:17054721
• BMC medical genetics • 2007 • Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes. PMID:17655765

Evidence Based Scoring (AI generated)