Browsing by Author "Dutcher, Susan K"

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    Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.
    (PLoS genetics, 2018-12-10) Bowie, Emily; Norris, Ryan; Anderson, Kathryn V; Goetz, Sarah C
    Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown. In this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis. A Ttbk2 allelic series revealed that upon partial reduction of full length TTBK2 function, TTBK2SCA11 can interfere with the activity of the residual wild-type protein to decrease cilia number and interrupt cilia-dependent Sonic hedgehog (SHH) signaling. Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. These studies provide a molecular foundation to understand the cellular and molecular pathogenesis of human SCA11, and help account for the link between ciliary dysfunction and neurodegenerative diseases.
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    Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
    (Nature communications, 2022-10) Selvaraj, Margaret Sunitha; Li, Xihao; Li, Zilin; Pampana, Akhil; Zhang, David Y; Park, Joseph; Aslibekyan, Stella; Bis, Joshua C; Brody, Jennifer A; Cade, Brian E; Chuang, Lee-Ming; Chung, Ren-Hua; Curran, Joanne E; de Las Fuentes, Lisa; de Vries, Paul S; Duggirala, Ravindranath; Freedman, Barry I; Graff, Mariaelisa; Guo, Xiuqing; Heard-Costa, Nancy; Hidalgo, Bertha; Hwu, Chii-Min; Irvin, Marguerite R; Kelly, Tanika N; Kral, Brian G; Lange, Leslie; Li, Xiaohui; Lisa, Martin; Lubitz, Steven A; Manichaikul, Ani W; Michael, Preuss; Montasser, May E; Morrison, Alanna C; Naseri, Take; O'Connell, Jeffrey R; Palmer, Nicholette D; Palmer, Nicholette D; Peyser, Patricia A; Reupena, Muagututia S; Smith, Jennifer A; Sun, Xiao; Taylor, Kent D; Tracy, Russell P; Tsai, Michael Y; Wang, Zhe; Wang, Yuxuan; Bao, Wei; Wilkins, John T; Yanek, Lisa R; Zhao, Wei; Arnett, Donna K; Blangero, John; Boerwinkle, Eric; Bowden, Donald W; Chen, Yii-Der Ida; Correa, Adolfo; Cupples, L Adrienne; Dutcher, Susan K; Ellinor, Patrick T; Fornage, Myriam; Gabriel, Stacey; Germer, Soren; Gibbs, Richard; He, Jiang; Kaplan, Robert C; Kardia, Sharon LR; Kim, Ryan; Kooperberg, Charles; Loos, Ruth JF; Viaud-Martinez, Karine A; Mathias, Rasika A; McGarvey, Stephen T; Mitchell, Braxton D; Nickerson, Deborah; North, Kari E; Psaty, Bruce M; Redline, Susan; Reiner, Alexander P; Vasan, Ramachandran S; Rich, Stephen S; Willer, Cristen; Rotter, Jerome I; Rader, Daniel J; Lin, Xihong; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Peloso, Gina M; Natarajan, Pradeep
    Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.