Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
Am J Hum Genet. 2012 Feb 10;90(2):308-13. doi: 10.1016/j.ajhg.2011.12.001. Epub 2012 Jan 19.
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.
漂浮港综合征（FHS）是一种罕见病症，其特征为身材矮小、骨骼成熟延迟、表达性语言障碍和独特的面部特征。该病通常为散发病例，但偶尔也有报告称存在亲代向子代的传递。我们采用外显子组测序，在五个无关联的散发 FHS 患者中发现了 SRCAP 的杂合截短突变。Sanger 测序在另外 8 个受影响的个体中发现了 SRCAP 突变。在所有 6 个可获得父母 DNA 的病例中，突变均为新生突变。SRCAP 是一种 SNF2 相关的染色质重塑因子，作为 CREB 结合蛋白（CREBBP，更为人所知的是 CBP，是 Rubinstein-Taybi 综合征 [RTS] 的主要病因）的共激活因子。共鉴定出 5 种 SRCAP 突变，其中两种是复发性的，均紧密聚集在最后一个外显子的一个小（111 个密码子）区域内。这些突变预计会破坏三个 C 末端 AT 钩 DNA 结合基序，同时保持 CBP 结合和 ATP 酶结构域的完整性。我们的研究结果表明，SRCAP 突变是 FHS 的主要病因，并为 FHS 和 RTS 之间的临床重叠提供了解释。
