Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation
Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation
复制标题
DOI：
10.1016/j.ajhg.2019.03.004
复制
发表时间：
2019-05-02
影响因子：
9.8
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Guo, Long;Bertola, Debora Romeo;Ikegawa, Shiro
集落刺激因子1受体（CSF 1 R）在调节单核细胞/巨噬细胞谱系（包括小胶质细胞和破骨细胞）的发育和功能中起关键作用。已知CSF 1 R的单等位基因突变可引起遗传性弥漫性白质脑病伴球状体（HDLS），这是一种成人发作的进行性神经退行性疾病。在这里，我们报告了七个受影响的个人从三个无关的家庭谁有双等位基因CSF 1 R突变。除了早发性高密度脂蛋白样神经系统疾病，他们有脑畸形和骨骼发育不良兼容的dysosteletion（DOS）或派尔病。我们确定了5个CSF 1 R突变是纯合子或复合杂合子在这些受影响的个人。其中两个是深度内含子突变，导致mRNA中内含子序列异常包含。与Csf 1 r基因敲除小鼠相比，受影响个体的骨骼和神经表型显得更温和和可变，这表明每个受影响个体中至少有一个突变是亚型的。我们的研究结果特征在于CSF 1 R缺陷引起的独特的人类骨骼表型，并暗示双等位基因CSF 1 R突变引起一系列神经和骨骼疾病，可能取决于CSF 1 R的残留功能。
Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.