Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria

A young man with polycythemia, reduced growth rate, persistent hypoglycemia, and mitochondrial defects first appearing at birth was found to have a synonymous homozygous mutation in VHL (c.222C -> A) that created a cryptic splice site leading to the production of a truncated VHL protein. Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C -> A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C -> T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.)