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PMID:24239381

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Citation

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 and Sidjanin, DJ (2013) 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. 93:1001-14

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.

Links

PubMed PMC3852926 Online version:10.1016/j.ajhg.2013.10.011

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PDIA4

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RAB18

involved_in

GO:0034389: lipid droplet organization

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q9NP72

P

Seeded From UniProt

complete

HUMAN:RB3GP

acts_upstream_of_or_within

GO:0034389: lipid droplet organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SC31A

located_in

GO:0030134: COPII-coated ER to Golgi transport vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RB3GP

involved_in

GO:0034389: lipid droplet organization

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q15042

P

Seeded From UniProt

complete

MOUSE:EEA1

located_in

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GOGA1

located_in

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BCL9

located_in

GO:0005801: cis-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0008584: male gonad development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0070309: lens fiber cell morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0072520: seminiferous tubule development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0034389: lipid droplet organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0007030: Golgi organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0007283: spermatogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0001675: acrosome assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

MOUSE:TBC20

involved_in

GO:0002088: lens development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856684

P

Seeded From UniProt

complete

HUMAN:RAB18

acts_upstream_of_or_within

GO:0034389: lipid droplet organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PDIA4

part_of

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:EEA1

part_of

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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