Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia

Asli Sirmaci, Michail Spiliopoulos, Francesco Brancati, Eric Powell, Duygu Duman, Alex Abrams, Guney Bademci, Emanuele Agolini, Shengru Guo, Berrin Konuk, Asli Kavaz, Susan H Blanton, Maria Christina Digilio, Bruno Dallapiccola, Juan Young, Stephan L Zuchner, Mustafa Tekin

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)289-294
Number of pages6
JournalAmerican Journal of Human Genetics
Volume89
Issue number2
DOIs
StatePublished - Aug 12 2011

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Intellectual Disability
Mutation
Ankyrin Repeat
Exome
Neurons
Neuronal Plasticity
Incisor
Cytoplasmic and Nuclear Receptors
Transcriptional Activation
Tooth
Central Nervous System
KBG syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. / Sirmaci, Asli; Spiliopoulos, Michail; Brancati, Francesco; Powell, Eric; Duman, Duygu; Abrams, Alex; Bademci, Guney; Agolini, Emanuele; Guo, Shengru; Konuk, Berrin; Kavaz, Asli; Blanton, Susan H; Digilio, Maria Christina; Dallapiccola, Bruno; Young, Juan; Zuchner, Stephan L; Tekin, Mustafa.

In: American Journal of Human Genetics, Vol. 89, No. 2, 12.08.2011, p. 289-294.

Research output: Contribution to journalArticle

Sirmaci, A, Spiliopoulos, M, Brancati, F, Powell, E, Duman, D, Abrams, A, Bademci, G, Agolini, E, Guo, S, Konuk, B, Kavaz, A, Blanton, SH, Digilio, MC, Dallapiccola, B, Young, J, Zuchner, SL & Tekin, M 2011, 'Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia', American Journal of Human Genetics, vol. 89, no. 2, pp. 289-294. https://doi.org/10.1016/j.ajhg.2011.06.007
Sirmaci, Asli ; Spiliopoulos, Michail ; Brancati, Francesco ; Powell, Eric ; Duman, Duygu ; Abrams, Alex ; Bademci, Guney ; Agolini, Emanuele ; Guo, Shengru ; Konuk, Berrin ; Kavaz, Asli ; Blanton, Susan H ; Digilio, Maria Christina ; Dallapiccola, Bruno ; Young, Juan ; Zuchner, Stephan L ; Tekin, Mustafa. / Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. In: American Journal of Human Genetics. 2011 ; Vol. 89, No. 2. pp. 289-294.
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