Molecular and computational analysis of a novel pathogenic variant in emopamil-binding protein (EBP) involved in cholesterol biosynthetic pathway causing a rare male EBP disorder with neurologic defects (MEND syndrome)

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.

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.

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.