Faculty Collaboration Database

Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet 2013 Dec 05;93(6):1001-14

Date

11/19/2013

Pubmed ID

24239381

Pubmed Central ID

PMC3852926

DOI

10.1016/j.ajhg.2013.10.011

Scopus ID

2-s2.0-84890310034 (requires institutional sign-in at Scopus site)   104 Citations

Abstract

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.

Author List

Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, Chang B, Morris-Rosendahl DJ, Carpanini S, Posmyk R, Harthill V, Sheridan E, Abdel-Salam GM, Terhal PA, Faravelli F, Accorsi P, Giordano L, Pinelli L, Hartmann B, Ebert AD, Barr FA, Aligianis IA, Sidjanin DJ

Authors

Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Danielle Sidjanin Maier PhD Nurse Practitioner in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Amino Acid Sequence
Animals
Base Sequence
Brain
Cataract
Cell Line
Cornea
DNA Mutational Analysis
Facies
Female
Fibroblasts
Humans
Hypogonadism
Infertility, Male
Intellectual Disability
Lens, Crystalline
Magnetic Resonance Imaging
Male
Mice
Microcephaly
Mutation
Optic Atrophy
Pedigree
Phenotype
Sequence Alignment
Testis
rab1 GTP-Binding Proteins