Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia

Am J Hum Genet. 2011 Aug 12;89(2):289-94. doi: 10.1016/j.ajhg.2011.06.007. Epub 2011 Jul 21.

Abstract

KBG syndrome is characterized by intellectual disability associated with macrodontia of the upper central incisors as well as distinct craniofacial findings, short stature, and skeletal anomalies. Although believed to be genetic in origin, the specific underlying defect is unknown. Through whole-exome sequencing, we identified deleterious heterozygous mutations in ANKRD11 encoding ankyrin repeat domain 11, also known as ankyrin repeat-containing cofactor 1. A splice-site mutation, c.7570-1G>C (p.Glu2524_Lys2525del), cosegregated with the disease in a family with three affected members, whereas in a simplex case a de novo truncating mutation, c.2305delT (p.Ser769GlnfsX8), was detected. Sanger sequencing revealed additional de novo truncating ANKRD11 mutations in three other simplex cases. ANKRD11 is known to interact with nuclear receptor complexes to modify transcriptional activation. We demonstrated that ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized, suggesting that it plays a role in neural plasticity. Our results demonstrate that mutations in ANKRD11 cause KBG syndrome and outline a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Bone Diseases, Developmental / complications*
  • Bone Diseases, Developmental / genetics
  • Bone and Bones / abnormalities*
  • Cell Nucleus / metabolism
  • Child
  • DNA Mutational Analysis
  • Exons / genetics
  • Facies
  • Female
  • Humans
  • Intellectual Disability / complications*
  • Intellectual Disability / genetics
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Protein Structure, Tertiary
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics*
  • Tooth Abnormalities / complications*
  • Tooth Abnormalities / genetics
  • Young Adult

Substances

  • ANKRD11 protein, human
  • Repressor Proteins

Supplementary concepts

  • KBG syndrome