BEND4 as a Candidate Gene for an Infection-Induced Acute Encephalopathy Characterized by a Cyst and Calcification of the Pons and Cerebellar Atrophy

Abstract

Three siblings born to Turkish parents from the same village had normal brain development until acute neurological deterioration between 12 months and 8 years of age. Consequent loss of all acquired motor, social, and language functionsfollowing infections was associated with a pontine cyst, calcification, and cerebellar atrophy. Exome sequencing revealed a homozygous c.1297G>A (p.Gly433Ser) alteration in BEND4, which was predicted to be deleterious in in silico analysistools and segregated in multiple affected individuals in the family. BEND4 has not been associated with any existing disease. Immunofluorescence microscopy analysis of wildtype and mutant BEND4 expressing Vero cells showed nuclearand cytoplasmic localization. Wild-type BEND4 displayed a network-like distribution, whereas mutant BEND4 showed a juxtanuclear distribution pattern. Differential proteome analysis of Vero cells expressing BEND4 revealed that mutantBEND4 expression caused selective increase in reticulocalbin- 1 and endoplasmic reticulum resident protein-29. Both proteins are associated with the endoplasmic reticulum and are primarily involved in protein processing and foldingpathways. Any defect or stress in protein folding creates stress on cells and may cause chronic damage. This is the first study showing that pathogenic BEND4 variants may lead to an infection-induced acute necrotizing encephalopathy asdemonstrated in characteristic neuroimaging findings.