title: Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.
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.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Asli
authors.initials: A
authors.lastname: Sirmaci
authors.forename: Michail
authors.initials: M
authors.lastname: Spiliopoulos
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Eric
authors.initials: E
authors.lastname: Powell
authors.forename: Duygu
authors.initials: D
authors.lastname: Duman
authors.forename: Alex
authors.initials: A
authors.lastname: Abrams
authors.forename: Guney
authors.initials: G
authors.lastname: Bademci
authors.forename: Emanuele
authors.initials: E
authors.lastname: Agolini
authors.forename: Shengru
authors.initials: S
authors.lastname: Guo
authors.forename: Berrin
authors.initials: B
authors.lastname: Konuk
authors.forename: Asli
authors.initials: A
authors.lastname: Kavaz
authors.forename: Susan
authors.initials: S
authors.lastname: Blanton
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Juan
authors.initials: J
authors.lastname: Young
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000150:complications* / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities*; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D019066:Facies; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics*; D014071:Tooth Abnormalities / Q000150:complications* / Q000235:genetics; D055815:Young Adult
chemical_list: C492515:ANKRD11 protein, human; D012097:Repressor Proteins