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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Loss-of-function mutations in TBC1d20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans
American Journal of Human Genetics, Volume 93, No. 6, Year 2013
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Description
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. © 2013 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3852926/bin/mmc1.pdf
Authors & Co-Authors
Liegel, Ryan P.
United States, Milwaukee
Medical College of Wisconsin
Handley, Mark T.W.
United Kingdom, Edinburgh
Mrc Human Genetics Unit
Ronchetti, Adam
United States, Milwaukee
Medical College of Wisconsin
Brown, Stephen D.M.
United Kingdom, Edinburgh
Mrc Human Genetics Unit
Langemeyer, Lars
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Linford, Andrea
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Chang, Bo
United States, Bar Harbor
The Jackson Laboratory
Morris-Rosendahl, Deborah J.
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
United Kingdom, London
National Heart and Lung Institute
Carpanini, Sarah
United Kingdom, Edinburgh
Mrc Human Genetics Unit
Posmyk, Renata
Poland, Bialystok
Uniwersytet Medyczny w Bialymstoku
Harthill, Verity
United Kingdom, Leeds
Chapel Allerton Hospital
Sheridan, Eamonn G.
United Kingdom, Leeds
Chapel Allerton Hospital
United Kingdom, Leeds
St James's University Hospital
Abdel-Salam, Ghada M.H.
Egypt, Giza
National Research Centre
Terhal, Paulien Anna
Netherlands, Utrecht
University Medical Center Utrecht
Faravelli, Francesca
Italy, Genoa
E.o. Ospedali Galliera
Accorsi, Patrizia
Unknown Affiliation
Giordano, Lucio
Unknown Affiliation
Pinelli, Lorenzo
Unknown Affiliation
Hartmann, Britta
Germany, Freiburg Im Breisgau
Universitätsklinikum Freiburg
Ebert, Allison D.
United States, Milwaukee
Medical College of Wisconsin
Barr, Francis A.
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Aligianis, Irene A.
United Kingdom, Edinburgh
Mrc Human Genetics Unit
Sidjanin, Duska J.
United States, Milwaukee
Medical College of Wisconsin
Statistics
Citations: 119
Authors: 23
Affiliations: 12
Identifiers
Doi:
10.1016/j.ajhg.2013.10.011
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Disability
Genetics And Genomics
Health System And Policy
Sexual And Reproductive Health
Study Design
Cohort Study
Participants Gender
Male