TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition

Stone, Steven; Abkevich, Victor; Russell, Deanna L.; Riley, Robyn; Timms, Kirsten M.; Tran, Thanh V.; Trem, Deborah J.; Frank, David A.; Jammulapati, Srikanth; Neff, Chris; Iliev, Diana; Gress, Richard E.; He, Gongping; Frech, Georges C.; Adams, Ted D.; Skolnick, Mark H.; Lanchbury, Jerry S.; Gutin, Alexander; Hunt, Steven C.; Shattuck, Donna

doi:10.1093/hmg/ddl204

Cited by 132 publications

(135 citation statements)

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“…34 Recently, a novel obesity linkage region was discovered by conditioning analysis on a SNP in TBC1D1, itself recently linked to obesity in the same pedigrees. 35 However, none of these conditional linkage analyses have led to a gene discovery. The HTR1A-conditional linkage of LHPP to MDD is the first for which a linked gene in an interacting region has been identified, and the first for which the gene-gene interaction has been further supported by showing conditional association in population studies.…”

Section: Discussionmentioning

confidence: 99%

“…These transcripts are shown in Figure 4. Expression levels were categorized according to threshold cycle: very high ( < 20), high (20)(21)(22)(23)(24)(25), moderate (25)(26)(27)(28)(29)(30), low (30)(31)(32)(33)(34)(35), very low/questionable (35)(36)(37)(38)(39)(40) or not detected (no signal above background after 40 cycles). Because of the linkage and association of LHPP variants to MDD, there was particular focus on measuring expression of these transcripts in the brain (Figure 3b).…”

Section: Serotonin Receptor 1a-conditional Genetic Analysismentioning

confidence: 99%

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Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

et al. 2008

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The HTR1A À1019C > G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A À1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD = 4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.

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Section: Discussionmentioning

confidence: 99%

Section: Serotonin Receptor 1a-conditional Genetic Analysismentioning

confidence: 99%

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

et al. 2008

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“…Tbc1d1, a critical protein associated with human obesity (19,25), was drastically reduced in the Tardbp deleted iTDPKO cells (−7.35 fold, P = 7.02E−228). As it has been reported that a nonfunctional Tbc1d1mutant in the skeletal muscle is responsible for the lean phenotype in mice and thatTbc1d1is essential for Glut4 translocation to the plasma membrane of skeletal muscle cells for glucose uptake (18), a decrease inTbc1d1 in skeletal muscle might offer an explanation for the lean phenotype shown in our conditional Tardp-KO mouse model (Fig.…”

Section: Marked Fat Loss and High Fatty Acid Consumption In Conditionalmentioning

confidence: 99%

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Chiang

Ling

Jeong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

266

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Tat activating regulatory DNA-binding protein (Tardbp or TDP-43), a highly conserved metazoan DNA/RNA binding protein thought to be involved in RNA transcription and splicing, has been linked to the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration and is essential for early embryonic development. However, neither the physiological role of TDP-43 in the adult nor its downstream targets are well defined. To address these questions, we developed conditional Tardbp-KO mice and embryonic stem (ES) cell models. Here, we show that postnatal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death. Moreover, conditional Tardbp-KO ES cells failed to proliferate. Importantly, high-throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. Collectively, our results establish that TDP-43 is critical for fat metabolism and ES cell survival.conditional knockout mice | amyotrophic lateral sclerosis | frontotemporal dementia | energy metabolism | RNA-sequencing I dentified initially as a cellular protein that regulates human immunodeficiency viral gene transcription (1), Tat activating regulatory DNA-binding protein (Tardbp or TDP-43) is a highly conserved DNA/RNA-binding protein thought to regulate alternative splicing of cystic fibrosis transmembrane conductance regulator (CFTR) and survival of motor neuron (SMN) through binding to heterogeneous nuclear ribonucleoprotein or (UG) n repeats of these target transcripts (2-4). Biophysical studies indicate that TDP-43 forms a dimer harboring two RNA-binding domains that preferentially bind to TG/UG repeats (5). Whereas TDP-43 is normally localized to the nucleus, it is redistributed as insoluble aggregates in neuronal nuclei, perikarya and neurites in amyotrophic lateral sclerosis (ALS) (6, 7) and frontotemporal lobar degeneration (FTLD) (8). The identification of missense mutations in TARDBP in familial and sporadic ALS (9, 10) supports the idea that this nuclear protein plays a critical role in the pathogenesis of these neurodegenerative disorders. Interestingly, most of these mutations identified to date are localized to the Cterminal domain of TDP-43, a heterogeneous nuclear ribonucleoprotein-interacting region that may be critical for the normal function of the protein. Although mutant TDP-43 mice showed evidence of neurodegeneration, no TDP-43-positive cytoplasmic aggregates were observed in neurons of these mutant mice, suggesting that altered RNA metabolism rather than TDP-43 aggregates underlies the pathogenesis of ALS or FTLD (11).To begin clarifying the molecular basis of mutant TDP-43-linked disease, it will be crucial to understand the physiological and cellular functions of TDP-43. Moreover, because increased expression of TDP-43 is also toxic to motor neurons (12, 13), it will be also important to identify a set ...

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“…The potential importance of Tbc1d1 in linking insulin, exercise and energy status signalling with GLUT4 membrane traffic is heightened by the additional recent discovery by Stone et al [13]. This group has reported that the gene coding for Tbc1d1 is a candidate severe obesity gene [13].…”

mentioning

confidence: 99%

“…This group has reported that the gene coding for Tbc1d1 is a candidate severe obesity gene [13]. A defect in this gene (leading to substitution of tryptophan for arginine) is present in some cases of severe obesity in females and gene-gene interaction studies have provided evidence that Tbc1d1 may give rise to obesity predisposition.…”

mentioning

confidence: 99%

Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

Koumanov

Holman

2007

Biochemical Journal

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Establishing a complete pathway which links occupancy of the insulin receptor to GLUT4 translocation has been particularly elusive because of the complexities involved in studying both signalling and membrane trafficking processes. However, Lienhard's group has now discovered two related molecules that could function in this linking role. These proteins, Tbc1d4 (also known as AS160) and now Tbc1d1, as reported in this issue of the Biochemical Journal, have been demonstrated to be Rab GAPs (GTPase-activating proteins) that link upstream to Akt (protein kinase B) and phosphoinositide 3-kinase and downstream to Rabs involved in trafficking of GLUT4 vesicles. The data from Leinhard and colleagues suggest that high levels of Rab GAP activity lead to suppression of GLUT4 translocation and this observation has wide significance and is likely to be relevant to the recent discovery that mutations in the Tbc1d1 gene lead to some cases of severe human obesity.

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TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition

Cited by 132 publications

References 44 publications

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

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