Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Genet Med. 2018 Jul;20(7):778-784. doi: 10.1038/gim.2017.113. Epub 2017 Aug 24.
To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.
A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.
All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.
LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.
阐明两个不相关的常染色体隐性智力障碍家系的新分子病因。
采用纯合子作图和外显子组测序相结合的方法定位家系 F162 中可能的遗传缺陷，而在家系 PKMR65 中仅采用外显子组测序。使用加利福尼亚大学旧金山 Chimera 软件可视化蛋白质 3D 结构。
两个家系的所有 5 名患者均表现为严重的智力障碍、攻击性行为、言语和运动发育迟缓。5 名患者中有 4 名存在小头畸形。我们在 F162 家系中发现了 LINGO1 的纯合错义变异，p.(Arg290His)，在 PKMR65 家系中发现了 p.(Tyr288Cys)。这两个变异均被预测为致病性的，且在家系中与表型共分离。LINGO1 的分子建模表明，这两个变异均干扰了蛋白的糖基化。
LINGO1 是一种跨膜受体，主要存在于中枢神经系统。在小鼠和斑马鱼中进行的功能丧失研究表明，LINGO1 通过负向调节少突胶质细胞分化和神经元存活，在正常神经元发育和中枢神经系统髓鞘形成中起着至关重要的作用。综上所述，我们的结果表明，LINGO1 的双等位基因突变导致人类常染色体隐性智力障碍。
