Rafiullah Rafiullah, Aslamkhan Muhammad, Paramasivam Nagarajan, Thiel Christian, Mustafa Ghulam, Wiemann Stefan, Schlesner Matthias, Wade Rebecca C, Rappold Gudrun A, Berkel Simone
Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
J Med Genet. 2016 Feb;53(2):138-44. doi: 10.1136/jmedgenet-2015-103179. Epub 2015 Nov 13.
Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause.
Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders.
This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder.
智力障碍（ID）是一种神经发育障碍，影响着全球1%-3%的人口。其特点是具有高度的表型和遗传异质性，在大多数情况下，该疾病的潜在病因尚不清楚。在我们的研究中，我们调查了一个来自巴基斯坦俾路支省的大家族，该家族中有7名患有严重常染色体隐性智力障碍（ARID）和癫痫的患者，以阐明可能的遗传病因。
对这个大家族中的一个三联体进行全外显子组测序（WES），该三联体包括一名患有智力障碍和癫痫的儿童及其健康父母，结果在凝集素甘露糖结合2样（LMAN2L）基因中发现了一个纯合错义变异p.R53Q。这个纯合变异在家族中与严重智力障碍和婴儿癫痫的表型共分离；未受影响的家庭成员是杂合变异携带者。该变异通过五个不同的计算机模拟程序被预测为致病的，并且对该蛋白质的进一步三维结构建模表明变异p.R53Q可能会损害蛋白质-蛋白质相互作用。LMAN2L（OMIM：609552）编码凝集素甘露糖结合2样蛋白，它是内质网中对糖蛋白运输很重要的货物受体。全基因组关联研究已经确定LMAN2L与不同的神经精神疾病有关联。
这是首次将LMAN2L与严重ARID和癫痫发作的表型联系起来的报告，表明有害的纯合p.R53Q变异很可能导致了该疾病。
