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Background  Loss-of-function mutations in  TBC1D20  cause Warburg Micro syndrome 4 (WARBM4), which is an autosomal recessive syndromic disorder characterized by eye, brain, and genital abnormalities.  Blind sterile  ( bs ) mice carry a  Tbc1d20-null  mutation and exhibit cataracts and testicular phenotypes similar to those observed in WARBM4 patients. In addition to  TBC1D20 , mutations in  RAB3GAP1, RAB3GAP2  and  RAB18  cause WARBM1-3 respectively. However, regardless of which gene harbors the causative mutation, all individuals affected with WARBM exhibit indistinguishable clinical presentations. In contrast,  bs, Rab3gap1   -/-   ,  and  Rab18   -/-   mice exhibit distinct phenotypes; this phenotypic variability of WARBM mice was previously attributed to potential compensatory mechanisms.  Rab3gap1   -/-   and  Rab18   -/-   mice were genetically engineered using standard approaches, whereas the  Tbc1d20  mutation in the  bs  mice arose spontaneously. There is the possibility that another unidentified mutation within the  bs  linkage disequilibrium may be contributing to the  bs  phenotypes and thus contributing to the phenotypic variability in WARBM mice. The goal of this study was to establish the phenotypic consequences in mice caused by the disruption of the  Tbc1d20  gene.    Results  The zinc finger nuclease (ZFN) mediated genomic editing generated a  Tbc1d20  c.[418_426del] deletion encoding a putative TBC1D20-ZFN protein with an in-frame p.[H140_Y143del] deletion within the highly conserved TBC domain. The evaluation of  Tbc1d20   ZFN/ZFN   eyes identified severe cataracts and thickened pupillary sphincter muscle.  Tbc1d20   ZFN/ZFN   males are infertile and the analysis of the seminiferous tubules identified disrupted acrosomal development. The compound heterozygote  Tbc1d20   ZFN/bs   mice, generated from an allelic  bs/+  X  Tbc1d20   ZFN/+   cross, exhibited cataracts and aberrant acrosomal development indicating a failure to complement.    Conclusions  Our findings show that the disruption of  Tbc1d20  in mice results in cataracts and aberrant acrosomal formation, thus establishing  bs  and  Tbc1d20   ZFN/ZFN   as allelic variants. Although the WARBM molecular disease etiology remains unclear, both the  bs  and  Tbc1d20   ZFN/ZFN   mice are excellent model organisms for future studies to establish TBC1D20-mediated molecular and cellular functions.

Targeted disruption of Tbc1d20with zinc-finger nucleases causes cataracts and testicular abnormalities in mice