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: Rebecca L Hood, Matthew A Lines, Sarah M Nikkel, Jeremy Schwartzentruber, Chandree Beaulieu, Małgorzata J M Nowaczyk, Judith Allanson, Chong Ae Kim, Dagmar Wieczorek, Jukka S Moilanen, Didier Lacombe, Gabriele Gillessen-Kaesbach, Margo L Whiteford, Caio Robledo D C Quaio, Israel Gomy, Debora R Bertola, Beate Albrecht, Konrad Platzer, George McGillivray, Ruobing Zou, D Ross McLeod, Albert E Chudley, Bernard N Chodirker, Janet Marcadier, FORGE Canada Consortium, Jacek Majewski, Dennis E Bulman, Susan M White, Kym M Boycott
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 90 Issue 2 Pg. 308-13 (Feb 10 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22265015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• CREB-Binding Protein
• CREBBP protein, human
• Adenosine Triphosphatases
• SRCAP protein, human

Topics

• Abnormalities, Multiple (genetics)
• Adenosine Triphosphatases (genetics)
• Amino Acid Motifs
• CREB-Binding Protein (genetics)
• Child
• Child, Preschool
• Chromatin (genetics)
• Craniofacial Abnormalities (genetics)
• Exome
• Female
• Growth Disorders (genetics)
• Heart Septal Defects, Ventricular (genetics)
• Heterozygote
• Humans
• Infant
• Male
• Mutation
• Phenotype
• Protein Binding
• Rubinstein-Taybi Syndrome (genetics)