De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

摘要: Summary Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms pediatric SRNS are predominantly caused by recessive mutations, while contribution de novo variants (DNVs) to this trait poorly understood. Using exome sequencing (ES) in proband with FSGS/SRNS, developmental delay, epilepsy, we discovered nonsense DNV TRIM8, which encodes E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 represent FSGS, aggregated exome/genome-sequencing data for 2,501 FSGS/SRNS-affected individuals 48,556 control subjects, detecting eight heterozygous truncating affected subjects but none (p = 3.28 × 10−11). In all six cases available parental DNA, demonstrated inheritance (p = 2.21 × 10−15). Reverse phenotyping revealed neurodevelopmental disease families. We next analyzed ES from 9,067 yielding three additional families variants. Clinical review FSGS all. All protein truncation clustering within last exon between residues 390 487 551 amino acid protein, indicating correlation loss C-terminal region. Wild-type overexpressed immortalized human podocytes neuronal cells localized nuclear bodies, constructs harboring patient-specific mislocalized diffusely nucleoplasm. Co-localization studies that Gemini Cajal bodies frequently abut body. Truncating DNVs neuro-renal via aberrant localization, implicating brain