Mutations in KCTD1 cause scalp-ear-nipple syndrome

Am J Hum Genet. 2013 Apr 4;92(4):621-6. doi: 10.1016/j.ajhg.2013.03.002. Epub 2013 Mar 28.

Abstract

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / etiology*
  • Abnormalities, Multiple / pathology
  • Amino Acid Sequence
  • Branchio-Oto-Renal Syndrome / etiology*
  • Branchio-Oto-Renal Syndrome / pathology
  • Ear, External / abnormalities
  • Ear, External / pathology
  • Ectodermal Dysplasia / etiology*
  • Ectodermal Dysplasia / pathology
  • Exome / genetics*
  • Female
  • Humans
  • Hypospadias / etiology*
  • Hypospadias / pathology
  • Male
  • Molecular Sequence Data
  • Muscle Hypotonia / etiology*
  • Muscle Hypotonia / pathology
  • Mutation, Missense / genetics*
  • Nipples / abnormalities
  • Nipples / pathology
  • Pedigree
  • Phenotype
  • Protein Structure, Tertiary
  • Repressor Proteins / genetics*
  • Scalp / abnormalities
  • Scalp / pathology
  • Sequence Homology, Amino Acid

Substances

  • KCTD1 protein, human
  • Repressor Proteins

Supplementary concepts

  • Scalp ear nipple syndrome