Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans.
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 bs locus to mouse chromosome 2. In this study, we first positionally cloned the bs locus and identified a putative causative mutation in the Tbc1d20 gene. Functional analysis established the mouse TBC1D20 protein as a GTPase-activating protein (GAP) for RAB1 and RAB2, and bs as a TBC1D20 loss-of-function mutation. Evaluation of bs mouse embryonic fibroblasts (mEFs) identified enlarged Golgi morphology and aberrant lipid droplet (LD) formation. Based on the function of TBC1D20 as a RABGAP and the bs cataract and testicular phenotypes, we hypothesized that mutations in TBC1D20 may contribute to Warburg micro syndrome (WARBM); WARBM constitutes a spectrum of disorders characterized by eye, brain, and endocrine abnormalities caused by mutations in RAB3GAP1, RAB3GAP2, and RAB18. Sequence analysis of a cohort of 77 families affected by WARBM identified five distinct TBC1D20 loss-of-function mutations, thereby establishing these mutations as causative of WARBM. Evaluation of human fibroblasts deficient in TBC1D20 function identified aberrant LDs similar to those identified in the bs mEFs. Additionally, our results show that human fibroblasts deficient in RAB18 and RAB3GAP1 function also exhibit aberrant LD formation. These findings collectively indicate that a defect in LD formation/metabolism may be a common cellular abnormality associated with WARBM, although it remains unclear whether abnormalities in LD metabolism are contributing to WARBM disease pathology.
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Ryan P
RP
Liegel
Mark T
MT
Handley
Adam
A
Ronchetti
Stephen
S
Brown
Lars
L
Langemeyer
Andrea
A
Linford
Bo
B
Chang
Deborah J
DJ
Morris-Rosendahl
Sarah
S
Carpanini
Renata
R
Posmyk
Verity
V
Harthill
Eamonn
E
Sheridan
Ghada M H
GM
Abdel-Salam
Paulien A
PA
Terhal
Francesca
F
Faravelli
Patrizia
P
Accorsi
Lucio
L
Giordano
Lorenzo
L
Pinelli
Britta
B
Hartmann
Allison D
AD
Ebert
Francis A
FA
Barr
Irene A
IA
Aligianis
Duska J
DJ
Sidjanin
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002386:Cataract / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003315:Cornea / Q000002:abnormalities* / Q000378:metabolism; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics*; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D007908:Lens, Crystalline / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009896:Optic Atrophy / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D013737:Testis / Q000473:pathology; D020761:rab1 GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
C526344:TBC1D20 protein, human; C586297:TBC1D20 protein, mouse; D020761:rab1 GTP-Binding Proteins