Bibi Hadiba, Ahmad Riaz, Rahman Fatima, Maqbool Shazia, Naeem Muhammad, Efthymiou Stephanie, Houlden Henry
Medical Genetics Research Laboratory, Department of Biotechnology, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
Department of Developmental & Behavioral Paediatrics, The Children's Hospital, University of Child Health Sciences, Lahore, Pakistan.
Mol Biol Rep. 2025 Jan 4;52(1):101. doi: 10.1007/s11033-024-10183-7.
Male EBP disorder with neurologic defects (MEND syndrome) is an extremely rare disorder with a prevalence of less than 1/1,000,000 individuals worldwide. It is inherited as an X-linked recessive disorder caused by impaired sterol biosynthesis due to nonmosaic hypomorphic EBP variants. MEND syndrome is characterized by variable clinical manifestations including intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. The goal of this study was to investigate the disease-causing variants in a family of two patients affected with MEND syndrome.
The genomic DNA of the two patients with MEND syndrome was subjected to whole exome sequencing to identify disease-causing variants. Segregation of the identified variant was tested through Sanger sequencing. Several in-silico tools were used to evaluate the pathogenicity of the variant. Protein's 3D structure analysis systems were used to predict the impact of the identified variant on the binding and function of the mutated EBP protein including AlphaFold, PyMOL, AutoDock, ChimeraX and Discovery Studio.
A novel pathogenic missense EBP variant NM_006579.3:c.556T > C (Trp186Arg) was found segregating in the affected family. In-silico analysis and molecular docking results supported the pathogenicity of the identified variant.
Our study expands the mutation spectrum of EBP and adds to the restricted reports of MEND patients. It strengthens the body of evidence that supports the role of EBP in the MEND syndrome phenotype. To our knowledge, this is the first report of this disorder from Pakistan.
男性伴有神经缺陷的EBP障碍（MEND综合征）是一种极其罕见的疾病，全球患病率低于百万分之一。它作为一种X连锁隐性疾病遗传，由非镶嵌性低表达EBP变体导致的固醇生物合成受损引起。MEND综合征的特征是临床表现多样，包括智力残疾、身材矮小、脊柱侧凸、手指异常、白内障和皮肤异常。本研究的目的是调查一个有两名MEND综合征患者的家庭中的致病变体。
对两名MEND综合征患者的基因组DNA进行全外显子测序，以鉴定致病变体。通过Sanger测序检测所鉴定变体的分离情况。使用几种电子工具评估变体的致病性。蛋白质的3D结构分析系统用于预测所鉴定变体对突变EBP蛋白的结合和功能的影响，包括AlphaFold、PyMOL、AutoDock、ChimeraX和Discovery Studio。
在受影响的家庭中发现了一种新的致病性错义EBP变体NM_006579.3:c.556T＞C（Trp186Arg）。电子分析和分子对接结果支持所鉴定变体的致病性。
我们的研究扩展了EBP的突变谱，并增加了对MEND患者的有限报道。它加强了支持EBP在MEND综合征表型中作用的证据。据我们所知，这是来自巴基斯坦的关于这种疾病的首次报告。
