Fig. 7. Illustrative examples of palindrome-mediated mechanisms of disease, as indicated in the literature.

a In certain subsets of bipolar disorder and schizophrenia patients, a mutation in the promoter region of PIK3C3 (−432C -> T) extends a 6-base palindrome (“TTTAAA”) into an 8-base palindrome (“ATTTAAAT”), which also acts as a 6/8 recognition sequence for POU domain transcription factors such as POU2F1 (OCT-1) and POU3F3 (BRN-1), whose consensus sequence is “ATTTGCAT”⁵¹. These transcription factors are regulators of brain development. Binding of POU domain transcription factors to the palindromic sequence may lead to the transcriptional activation of PIK3C3 and PIK3C3-mediated neurodevelopmental changes. b X-linked congenital generalized hypertrichosis is a rare genetic condition characterized by hair overgrowth over the entire body. In families in which this condition is segregated, chromosomal breakpoints are observed in a 180-base palindromic sequence located 82 kb downstream of the SOX3 gene on Xq27.1⁵². SOX (SRY-related HMG-box) transcription factors are regulators of embryonic development. The 180-base palindromic sequence mediates an interchromosomal insertion of either a 125,577 bp fragment from COL23A1 of 5q35.3 or a 300,036 bp fragment from 4q31.2 (including the genes PRMT9 and TMEM184C and sections of EDNRA and ARHGAP10) into these breaks. New regulatory elements may be introduced with the insertion of these fragments. It has been conjectured that, as a result of these new elements, SOX3 may be ectopically expressed in hair follicles or precursor cells during the early stages of hair follicle development. Structures of chromosomes 18 and X, and gene structures of PIK3C3, SOX3, COL23A1, PRMT9, TMEM184C, EDNRA, and ARHGAP10 were taken from UCSC Genome Browser (https://genome.ucsc.edu/)⁵³. The images were produced based on the GRCh38 (hg38) assembly. The protein structure of POU2F1⁵⁴ (PDB ID: 1OCT) was downloaded from RCSB PDB⁵⁵. The image of POU2F1 was created using UCSF Chimera⁵⁶.