A misplaced lncRNA causes brachydactyly in humans

J Clin Invest. 2012 Nov;122(11):3990-4002. doi: 10.1172/JCI65508. Epub 2012 Oct 24.


Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brachydactyly* / diagnostic imaging
  • Brachydactyly* / genetics
  • Brachydactyly* / metabolism
  • Chromosomes, Human, Pair 12* / genetics
  • Chromosomes, Human, Pair 12* / metabolism
  • Chromosomes, Human, Pair 17*
  • Female
  • Gene Expression Regulation*
  • Gene Silencing
  • Genetic Loci*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Parathyroid Hormone-Related Protein / biosynthesis
  • Parathyroid Hormone-Related Protein / genetics
  • RNA, Long Noncoding* / biosynthesis
  • RNA, Long Noncoding* / genetics
  • Radiography
  • SOX9 Transcription Factor / biosynthesis
  • SOX9 Transcription Factor / genetics
  • Translocation, Genetic*


  • PTHLH protein, human
  • Parathyroid Hormone-Related Protein
  • RNA, Long Noncoding
  • SOX9 Transcription Factor
  • SOX9 protein, human