title: Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.
abstract: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hood
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lines
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nikkel
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Chandree
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Małgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Judith
authors.initials: J
authors.lastname: Allanson
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Margo L
authors.initials: ML
authors.lastname: Whiteford
authors.forename: Caio Robledo D C
authors.initials: CR
authors.lastname: Quaio
authors.forename: Israel
authors.initials: I
authors.lastname: Gomy
authors.forename: Debora R
authors.initials: DR
authors.lastname: Bertola
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Konrad
authors.initials: K
authors.lastname: Platzer
authors.forename: George
authors.initials: G
authors.lastname: McGillivray
authors.forename: Ruobing
authors.initials: R
authors.lastname: Zou
authors.forename: D Ross
authors.initials: DR
authors.lastname: McLeod
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Bernard N
authors.initials: BN
authors.lastname: Chodirker
authors.forename: Janet
authors.initials: J
authors.lastname: Marcadier
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Susan M
authors.initials: SM
authors.lastname: White
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D020816:Amino Acid Motifs; D050882:CREB-Binding Protein / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D059472:Exome; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics
chemical_list: D002843:Chromatin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D000251:Adenosine Triphosphatases; C119652:SRCAP protein, human