Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10 Ave, BRB 610, M-860, Miami, FL, 33136, USA,
Hum Genet. 2015 Feb;134(2):181-90. doi: 10.1007/s00439-014-1509-2. Epub 2014 Nov 21.
Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.
ANKRD11 中的突变最近被报道可导致 KBG 综合征，这是一种常染色体显性疾病，其特征为智力残疾（ID）、行为问题和巨齿症。为了了解 ANKRD11 突变与 KBG 综合征表型相关的致病机制，我们研究了野生型 ANKRD11 的细胞特征以及人类和小鼠突变的影响。我们表明，在细胞周期中，野生型 ANKRD11 的丰度受到严格调控，ANKRD11 的 C 端对于蛋白质的降解是必需的。对 11 种人类致病性 ANKRD11 变体（包括本研究中报道的 6 种和 Ankrd11（Yod/+）小鼠中报道的 1 种）的分析表明，所有突变均影响 C 末端区域，并且突变蛋白异常积累。计算机分析表明存在 D 盒序列，这是蛋白酶体降解的信号。我们认为 ANKRD11 C 端在调节蛋白质丰度方面起着重要作用，由于突变导致蛋白质丰度的紊乱导致 KBG 综合征。
