Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

摘要: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous are expected to be phenotypically silent their role in remains poorly understood. We report Caucasian male with family history pheochromocytoma synonymous c.414A > G (p.Pro138Pro). At 47-years, MRI revealed left adrenal gland hemangioblastomas spine brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed craniotomy resection were needed reduce residual lesions. Two three proband’s children inherited both presented retinal without at age 7: one twin four laser treatments. Primary skin fibroblasts carrying heterozygous or wild type established family. Mutant downregulated full-length mRNA protein, upregulated short isoform (a result exon 2 skipping splicing) level but not protein level. Our study shows can within 7 years induce pediatric hemangioblastoma absence pheochromocytoma. This highlights need splicing-altering into screening for disease. also first on detecting validating using patient-derived fibroblasts. The translates p.Pro138Pro, yet it functionally silent, because causes aberrant splicing 2. reduced completely abolished pVHL loss-of-heterozygosity genetic backdrop may underlie etiology