Rapp-Hodgkin syndrome and SHFM1 patients: delineating the p63-Dlx5/Dlx6 pathway

Gene. 2012 Apr 15;497(2):292-7. doi: 10.1016/j.gene.2012.01.088. Epub 2012 Feb 9.

Abstract

Rapp-Hodgkin Syndrome (RHS) is a genetic disorder resulting from mutations in the TP63 gene encoding p63 transcription factor. p63 is directly associated with a cis-regulatory element on chromosome 7q21 that controls the expression of DLX5 and DLX6 genes which are involved in craniofacial abnormalities and ectrodactyly or split hand/foot malformation (SHFM). Chromosomal deletions on 7q21 locus can result in loss of DXL5/DLX6 and/or in loss/disruption of cis-regulatory elements, at which p63 binds. We report two patients that have in common a p63-Dlx5/Dlx6 pathway dysregulation. One showed growth retardation, craniofacial dysmorphism, syndactyly, developmental delay and a de novo deletion (~8.5Mb) on chromosome 7q21.13-q21.3, including DLX5 and DLX6. The second patient with a clinical diagnosis of RHS showed a de novo heterozygous missense mutation, c. 401G>A (p.G134D), in TP63 (exon 4). Our findings may contribute to a greater understanding of the pathogenic mechanisms underlying disorders caused by TP63 mutations.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Child, Preschool
  • Chromosome Deletion
  • Chromosomes, Human, Pair 7 / genetics
  • Cleft Lip / genetics*
  • Cleft Lip / metabolism
  • Cleft Palate / genetics*
  • Cleft Palate / metabolism
  • Craniofacial Abnormalities / genetics
  • Craniofacial Abnormalities / metabolism
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / metabolism
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Infant
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / metabolism
  • Male
  • Mutation, Missense / genetics
  • Proteasome Endopeptidase Complex / genetics*
  • Sequence Deletion / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • DLX5 protein, human
  • DLX6 protein, human
  • Homeodomain Proteins
  • SEM1 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Proteasome Endopeptidase Complex

Supplementary concepts

  • Rapp-Hodgkin syndrome
  • Split hand foot deformity