Homozygous truncating PTPRF mutation causes athelia

Hum Genet. 2014 Aug;133(8):1041-7. doi: 10.1007/s00439-014-1445-1. Epub 2014 Apr 30.


Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear-nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell-cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple-areola region.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Breast / abnormalities*
  • Breast / pathology
  • Breast Diseases
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Congenital Abnormalities / etiology*
  • Congenital Abnormalities / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Frameshift Mutation / genetics*
  • Gene Expression Profiling*
  • Genome-Wide Association Study
  • Homozygote*
  • Humans
  • Infant
  • Male
  • Mice
  • Nipples / metabolism
  • Nipples / pathology
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics*


  • PTPRF protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2

Supplementary concepts

  • Amastia