Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. 2423 81

Warburg Micro Syndrome (WARBM, MIM 600118) is a rare, severe autosomal recessive neurodevelopmental disorder characterized by microcephaly, microphthalmia, microcornea, congenital cataract, cortical dysplasia, corpus callosum hypoplasia, intellectual disability, hypotonia and hypogonadism. RABS, small G proteins belonging to the RAS superfamily, are master regulators of vesicle trafficking in the cell. The identification of mutations in the RAB3GAP1 and RAB3GAP2 genes, which together encode the RAB3GTPase-activating protein, a key regulator in calcium-mediated exocytosis of neurotransmitters and hormones, has underpinned abnormal development of the brain, eye and genitalia as cardinal features of this syndrome. More than 100 patients have been reported with WARBM, with mutations in the RABGAP1, RABGAP2, RAB18 and TBC1D20 genes. The objective of the study was to describe the recurrent RAB3GAP1 mutations and compare the clinical features of the patients with WARBM in the Turkish population. Here we report two brothers with Warburg Micro Syndrome 1 from a non-consanguineous Turkish family with clinical features similar to those previously reported in Turkish patients with RAB3GAP1 mutations. We found that the c.748+1G>A splice-site mutation in RAB3GAP1 intron 8 is common and has so far only been detected in patients of Turkish ethnic origin. Although one of our patients has a distal extra crease on the 4th finger and another has nephrolithiasis, there does not appear to be any specific phenotypic findings associated with this mutation.
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PMID:RECURRENT RAB3GAP1 MUTATIONS IN THE TURKISH POPULATION. 2685 12