Loss-of-Function Mutations in TBC1D20 Cause Cataracts and Male Infertility in blind sterile Mice and Warburg Micro Syndrome in Humans

摘要: blind sterile (bs) is a spontaneous autosomal-recessive mouse mutation discovered more than 30 years ago. Phenotypically, bs mice exhibit nuclear cataracts and male infertility; genetic analyses assigned the locus to chromosome 2. In this study, we first positionally cloned identified putative causative in Tbc1d20 gene. Functional analysis established TBC1D20 protein as GTPase-activating (GAP) for RAB1 RAB2, loss-of-function mutation. Evaluation of embryonic fibroblasts (mEFs) enlarged Golgi morphology aberrant lipid droplet (LD) formation. Based on function RABGAP cataract testicular phenotypes, hypothesized that mutations may contribute Warburg micro syndrome (WARBM); WARBM constitutes spectrum disorders characterized by eye, brain, endocrine abnormalities caused RAB3GAP1, RAB3GAP2, RAB18. Sequence cohort 77 families affected five distinct mutations, thereby establishing these WARBM. human deficient LDs similar those mEFs. Additionally, our results show RAB18 RAB3GAP1 also LD These findings collectively indicate defect formation/metabolism be common cellular abnormality associated with WARBM, although it remains unclear whether metabolism are contributing disease pathology.