141 results on '"Lifton, Richard P."'
Search Results
2. A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family.
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Gauhar, Zeeshan, Tejwani, Leon, Abdullah, Uzma, Saeed, Sadia, Shafique, Shagufta, Badshah, Mazhar, Choi, Jungmin, Dong, Weilai, Nelson-Williams, Carol, Lifton, Richard P., Lim, Janghoo, and Raja, Ghazala K.
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CEREBELLAR ataxia ,MISSENSE mutation ,MAGNETIC resonance imaging ,YOUNG adults ,PROTEIN structure ,PROTEIN stability - Abstract
Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Quantifying concordant genetic effects of de novo mutations on multiple disorders.
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Hanmin Guo, Lin Hou, Yu Shi, Sheng Chih Jin, Xue Zeng, Boyang Li, Lifton, Richard P., Brueckner, Martina, Hongyu Zhao, and Qiongshi Lu
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- 2022
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4. Mutation spectrum of congenital heart disease in a consanguineous Turkish population.
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Dong, Weilai, Kaymakcalan, Hande, Jin, Sheng Chih, Diab, Nicholas S., Tanıdır, Cansaran, Yalcin, Ali Seyfi Yalim, Ercan‐Sencicek, A. Gulhan, Mane, Shrikant, Gunel, Murat, Lifton, Richard P., Bilguvar, Kaya, and Brueckner, Martina
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CONSANGUINITY ,CONGENITAL heart disease ,GENETIC mutation - Abstract
Backgrounds: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts. Methods: We recruited 73 CHD probands from consanguineous families in Turkey and used whole‐exome sequencing (WES) to identify genetic lesions in these patients. Results: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss‐of‐function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D‐TGA). Three additional patients (4.1%) harbored other types of CHD‐associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity. Conclusions: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.
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Timberlake, Andrew T., Junn, Alexandra, Flores, Roberto, Staffenberg, David A., Lifton, Richard P., and Persing, John A.
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- 2022
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6. Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders.
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Calpena, Eduardo, Wurmser, Maud, McGowan, Simon J., Atique, Rodrigo, Bertola, Débora R., Cunningham, Michael L., Gustafson, Jonas A., Johnson, David, Morton, Jenny E. V., Passos-Bueno, Maria Rita, Timberlake, Andrew T., Lifton, Richard P., Wall, Steven A., Twigg, Stephen R. F., Maire, Pascal, and Wilkie, Andrew O. M.
- Abstract
Background Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported. Methods We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse. Results From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme. Conclusion Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis. [ABSTRACT FROM AUTHOR]
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- 2022
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7. The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.
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Sun, Qisi, Burgren, Nareh M., Cheraghlou, Shayan, Paller, Amy S., Larralde, Margarita, Bercovitch, Lionel, Levinsohn, Jonathan, Ren, Ivy, Hu, Rong Hua, Zhou, Jing, Zaki, Theodore, Fan, Ryan, Tian, Charlie, Saraceni, Corey, Nelson-Williams, Carol J., Loring, Erin, Craiglow, Brittany G., Milstone, Leonard M., Lifton, Richard P., and Boyden, Lynn M.
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- 2022
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8. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+).
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Seidel, Eric, Schewe, Julia, Junhui Zhang, Hoang An Dinh, Forslund, Sofia K., Markó, Lajos, Hellmig, Nicole, Peters, Jörg, Muller, Dominik N., Lifton, Richard P., Nottoli, Timothy, Stöltinga, Gabriel, and Scholl, Ute I.
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HYPERALDOSTERONISM ,RENIN-angiotensin system ,HIGH-salt diet ,SYSTOLIC blood pressure ,GAIN-of-function mutations ,COMMERCIAL products - Abstract
Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel CaV3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1h
M1560V/+ knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h-/-). Adrenal morphology of both Cacna1hM1560V/+ and Cacna1h-/- mice was normal. Cacna1hM1560V/+ mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1hM1560V/+ mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h-/- mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of CaV3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1hM1560V/+ adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca2+ concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of CaV3.2 channel function can be compensated for in a chronic setting. [ABSTRACT FROM AUTHOR]- Published
- 2021
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9. Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency.
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Ward, Tarsha, Tai, Warren, Morton, Sarah, Impens, Francis, Van Damme, Petra, Van Haver, Delphi, Timmerman, Evy, Venturini, Gabriela, Zhang, Kehan, Jang, Min Young, Willcox, Jon A.L., Haghighi, Alireza, Gelb, Bruce D., Chung, Wendy K., Goldmuntz, Elizabeth, Porter, George A., Lifton, Richard P., Brueckner, Martina, Yost, H. Joseph, and Bruneau, Benoit G.
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- 2021
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10. Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.
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Morton, Sarah U., Shimamura, Akiko, Newburger, Peter E., Opotowsky, Alexander R., Quiat, Daniel, Pereira, Alexandre C., Jin, Sheng Chih, Gurvitz, Michelle, Brueckner, Martina, Chung, Wendy K., Shen, Yufeng, Bernstein, Daniel, Gelb, Bruce D., Giardini, Alessandro, Goldmuntz, Elizabeth, Kim, Richard W., Lifton, Richard P., Porter, George A., Srivastava, Deepak, and Tristani-Firouzi, Martin
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- 2021
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11. Late-Onset Bartter Syndrome Type II Due to a Homozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review.
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Elfert, Khaled A., Geller, David S., Nelson-Williams, Carol, Lifton, Richard P., Al-Malki, Hassan, and Nauman, Awais
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GENETIC mutation ,LITERATURE reviews ,POLYHYDRAMNIOS ,HYPOKALEMIA ,GENETIC disorders ,SYNDROMES ,MISSENSE mutation - Abstract
Objective: Unusual clinical course. Background: Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. Case Report: Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. Conclusions: To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter's Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation. [ABSTRACT FROM AUTHOR]
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- 2020
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12. A genome-wide case-only test for the detection of digenic inheritance in human exomes.
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Kerner, Gaspard, Bouaziz, Matthieu, Cobat, Aurélie, Bigio, Benedetta, Timberlake, Andrew T., Bustamante, Jacinta, Lifton, Richard P., Casanova, Jean-Laurent, and Abel, Laurent
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FALSE positive error ,EXOMES ,LINKAGE disequilibrium - Abstract
Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene × gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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13. Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea.
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Gao, Emily, Cheema, Huma, Waheed, Nadia, Mushtaq, Iqra, Erden, Nihan, Nelson‐Williams, Carol, Jain, Dhanpat, Soroka, Carol J., Boyer, James L., Khalil, Youssef, Clayton, Peter T., Mistry, Pramod K., Lifton, Richard P., and Vilarinho, Sílvia
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- 2020
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14. EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.
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Hsieh, Alexander, Morton, Sarah U., Willcox, Jon A. L., Gorham, Joshua M., Tai, Angela C., Qi, Hongjian, DePalma, Steven, McKean, David, Griffin, Emily, Manheimer, Kathryn B., Bernstein, Daniel, Kim, Richard W., Newburger, Jane W., Porter, George A., Srivastava, Deepak, Tristani-Firouzi, Martin, Brueckner, Martina, Lifton, Richard P., Goldmuntz, Elizabeth, and Gelb, Bruce D.
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CONGENITAL heart disease ,FETAL echocardiography ,MOSAICISM - Abstract
Background: The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods: We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results: EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. Conclusions: We estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing.
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Dong, Weilai, Baldwin, Clinton, Choi, Jungmin, Milunsky, Jeff M., Zhang, Junhui, Bilguvar, Kaya, Lifton, Richard P., and Milunsky, Aubrey
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MYOSIN ,SMOOTH muscle contraction ,RECESSIVE genes ,EXTENDED families ,SMOOTH muscle ,NEMALINE myopathy ,GASTROINTESTINAL system ,DYSPLASIA - Abstract
Chronic Intestinal Pseudo‐Obstruction (CIPO) is a rare gastrointestinal disorder, which affects the smooth muscle contractions of the gastrointestinal tract. Dominant mutations in the smooth muscle actin gene, ACTG2, accounts for 44%‐50% of CIPO patients. Other recessive or X‐linked genes, including MYLK, LMOD1, RAD21, MYH11, MYL9, and FLNA were reported in single cases. In this study, we used Whole‐Exome Sequencing (WES) to study 23 independent CIPO families including one extended family with 13 affected members. A dominantly inherited rare mutation, c.5819delC (p.Pro1940HisfsTer91), in the smooth muscle myosin gene, MYH11, was found in the extended family, shared by 7 affected family members but not by 3 unaffected family members with available DNA, suggesting a high probability of genetic linkage. Gene burden analysis indicates that additional genes, COL4A1, FBLN1 and HK2, may be associated with the disease. This study expanded our understanding of CIPO etiology and provided additional genetic evidence to physicians and genetic counselors for CIPO diagnosis. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.
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Wantanabe, Miho, Zhang, Jinwei, Mansuri, M. Shahid, Duan, Jingjing, Karimy, Jason K., Delpire, Eric, Alper, Seth L., Lifton, Richard P., Fukuda, Atsuo, and Kahle, Kristopher T.
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CENTRAL nervous system ,PHOSPHORYLATION ,NEUROLOGICAL disorders ,STATUS epilepticus ,THREONINE ,RESPONSE inhibition ,CHONDROITIN sulfate proteoglycan - Abstract
KCC2 in neuronal maturity: High intracellular concentrations of Cl
− ions in neurons interfere with synaptic signaling, particularly of the inhibitory neurotransmitter of the central nervous system (CNS), γ-aminobutyric acid (GABA), and are implicated in several neurological diseases, such as epilepsy and schizophrenia. By extruding Cl− ions, the K+ /Cl− cotransporter KCC2 (encoded by SLC12A5) helps maintain Cl− homeostasis. Watanabe et al. and Pisella et al. (see also the Focus by Zamponi) developed two knockin mouse models of constitutive KCC2 phosphorylation at two threonine sites and examined the consequential neurodevelopmental effects. Their findings show that dephosphorylation of these sites in KCC2 during CNS development in the mouse contributes to the GABA excitatory-to-inhibitory switch that promotes the neurocircuitry that underlies cognition, respiration, and other critical neurological physiology, thereby elucidating the causes of KCC2 (SLC12A5)–related pathologies. Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K+ /Cl− cotransporter KCC2 (encoded by SLC12A5) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr906 and Thr1007 , which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing the homozygous phosphomimetic KCC2 mutations T906E/T1007E (Kcc2E/E ), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. Kcc2E/E mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl− extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival. [ABSTRACT FROM AUTHOR]- Published
- 2019
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17. COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.
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Kitzler, Thomas M., Schneider, Ronen, Kohl, Stefan, Kolvenbach, Caroline M., Connaughton, Dervla M., Dai, Rufeng, Mann, Nina, Nakayama, Makiko, Majmundar, Amar J., Wu, Chen-Han W., Kari, Jameela A., El Desoky, Sherif M., Senguttuvan, Prabha, Bogdanovic, Radovan, Stajic, Natasa, Valivullah, Zaheer, Lek, Monkol, Mane, Shrikant, Lifton, Richard P., and Tasic, Velibor
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RETINAL artery ,URINARY organs ,VESICO-ureteral reflux ,MISSENSE mutation ,NEPHROTIC syndrome - Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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18. Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3.
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Allocco, August A., Jin, Sheng Chih, Duy, Phan Q., Furey, Charuta G., Zeng, Xue, Dong, Weilai, Nelson-Williams, Carol, Karimy, Jason K., DeSpenza, Tyrone, Hao, Le T., Reeves, Benjamin, Haider, Shozeb, Gunel, Murat, Lifton, Richard P., and Kahle, Kristopher T.
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BRAIN abnormalities ,NEMALINE myopathy ,NEURAL stem cells ,HYDROCEPHALUS ,ARNOLD-Chiari deformity ,CORPUS callosum - Abstract
Background: ATP1A3 encodes the α3 subunit of the Na
+ /K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH). Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize Atp1a3 expression during brain development. Results: We identified two germline mutations in ATP1A3 (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient's unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust Atp1a3 expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain. Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in ATP1A3 , and implicate impaired Na+ /K+ ATPase function in the pathogenesis of CH. [ABSTRACT FROM AUTHOR]- Published
- 2019
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19. Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.
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Timberlake, Andrew T., Sheng Chih Jin, Nelson-Williams, Carol, Wu, Robin, Furey, Charuta G., Islam, Barira, Haider, Shozeb, Loring, Erin, Galm, Amy, Steinbacher, Derek M., Larysz, Dawid, Staffenberg, David A., Flores, Roberto L., Rodriguez, Eduardo D., Boggon, Titus J., Persing, John A., and Lifton, Richard P.
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CRANIOSYNOSTOSES ,CRANIAL sutures ,NEURAL crest ,GENES - Abstract
Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 x 10
-8 ); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 x 10-12 ). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing. [ABSTRACT FROM AUTHOR]- Published
- 2019
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20. Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility.
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Robson, Andrew, Makova, Svetlana Z., Barish, Syndi, Zaidi, Samir, Mehta, Sameet, Drozd, Jeffrey, Sheng Chih Jin, Gelb, Bruce D., Seidman, Christine E., Chung, Wendy K., Lifton, Richard P., Khokha, Mustafa K., and Brueckner, Martina
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CILIA & ciliary motion ,HEART development ,HUMAN chromatin ,CONGENITAL heart disease ,TRANSCRIPTION factors ,CARDIAC patients - Abstract
Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution frommutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40, and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment 6.01, P = 1.67 × 10
−03 ), some of whom had abnormal laterality associated with ciliary dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right (LR) asymmetry, and impaired cilia motility. Rnf20, Rnf40, and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and nonciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3. Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissuespecific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function. [ABSTRACT FROM AUTHOR]- Published
- 2019
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21. Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis.
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Ünlüsoy Aksu, Aysel, Das, Subhash K., Nelson‐Williams, Carol, Jain, Dhanpat, Özbay Hoşnut, Ferda, Evirgen Şahin, Gülseren, Lifton, Richard P., and Vilarinho, Silvia
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CHOLESTASIS ,LIVER diseases ,CHOLESTASIS in newborn infant - Abstract
Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma‐glutamyltransferase (GGT) cholestasis. Here, we report whole‐exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 (KIF12). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion: Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children. Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children high gamma‐glutamyltransferase (GGT) cholestasis. Here, we studied 3 children from 2 unrelated consanguineous families with high GGT cholestasis of unclear etiology and found that their underlying liver disease is due to recessive mutations in KIF12, which encodes kinesis family member 12. [ABSTRACT FROM AUTHOR]
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- 2019
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22. Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.
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Ishizawa, Kenichi, Qin Wang, Jinping Li, Yamazaki, Osamu, Tamura, Yoshifuru, Fujigaki, Yoshihide, Uchida, Shunya, Lifton, Richard P., and Shibat, Shigeru
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CALCINEURIN ,DEPHOSPHORYLATION ,ANGIOTENSINS ,GERM cells ,GENETIC mutation ,UBIQUITIN ligases - Abstract
Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)- CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3
S433-P ) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3S433-P dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3S433-P phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3S433-P levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3S433-P , resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3- mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K+ induced calcineurin-dependent dephosphorylation of KLHL3S433-P . These findings demonstrate that KLHL3S433-P is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies. [ABSTRACT FROM AUTHOR]- Published
- 2019
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23. Clonal evolution analysis of paired anaplastic and well‐differentiated thyroid carcinomas reveals shared common ancestor.
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Dong, Weilai, Nicolson, Norman G., Choi, Jungmin, Barbieri, Andrea L., Kunstman, John W., Abou Azar, Sara, Knight, James, Bilguvar, Kaya, Mane, Shrikant M., Lifton, Richard P., Korah, Reju, and Carling, Tobias
- Published
- 2018
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24. ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor.
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Shibata, Shigeru, Ishizawa, Kenichi, Wang, Qin, Xu, Ning, Fujita, Toshiro, Uchida, Shunya, and Lifton, Richard P.
- Abstract
Summary Mineralocorticoid receptor (MR) signaling regulates both renal Na-Cl reabsorption and K + excretion. We previously demonstrated that phosphorylation of S843 in the MR ligand-binding domain in renal intercalated cells is involved in the balance of these activities by regulating ligand binding and signaling. However, the kinase that phosphorylates MR S843 is unknown. Using a high-throughput screen assay of 197 kinases, we found that ULK1 is the principal kinase that is responsible for the phosphorylation of MR S843 . The results were confirmed by in vitro kinase assay, mass spectrometry, and siRNA knockdown experiments. Notably, phosphorylation at MR S843 was markedly reduced in ULK1/2 double knockout mouse embryonic fibroblasts. Upstream, we show that ULK1 activity is inhibited by phosphorylation induced by angiotensin II via mTOR in cell culture and in vivo . These findings implicate mTOR and ULK1 as regulators of MR activity in intercalated cells, a pathway that is critical for maintaining electrolyte homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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25. Robust identification of mosaic variants in congenital heart disease.
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Manheimer, Kathryn B., Richter, Felix, Edelmann, Lisa J., D'souza, Sunita L., Shi, Lisong, Shen, Yufeng, Homsy, Jason, Boskovski, Marko T., Tai, Angela C., Gorham, Joshua, Yasso, Christopher, Goldmuntz, Elizabeth, Brueckner, Martina, Lifton, Richard P., Chung, Wendy K., Seidman, Christine E., Seidman, J. G., and Gelb, Bruce D.
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MOSAICISM ,SOMATIC mutation ,NEURODEVELOPMENTAL treatment ,CONGENITAL heart disease ,PREVENTION ,VIRUSES - Abstract
Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (
n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaicKMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology. [ABSTRACT FROM AUTHOR]- Published
- 2018
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26. The Congenital Heart Disease Genetic Network Study: Cohort description.
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Hoang, Thanh T., Goldmuntz, Elizabeth, Roberts, Amy E., Chung, Wendy K., Kline, Jennie K., Deanfield, John E., Giardini, Alessandro, Aleman, Adolfo, Gelb, Bruce D., Mac Neal, Meghan, Jr.Porter, George A., Kim, Richard, Brueckner, Martina, Lifton, Richard P., Edman, Sharon, Woyciechowski, Stacy, Mitchell, Laura E., and Agopian, A. J.
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CONGENITAL heart disease ,PHENOTYPES ,GENOTYPES ,MEDICAL records ,COHORT analysis ,GENETICS - Abstract
The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010–2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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27. De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.
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Timberlake, Andrew T., Furey, Charuta G., Jungmin Choi, Nelson-Williams, Carol, Loring, Erin, Galm, Amy, Kahle, Kristopher T., Steinbacher, Derek M., Larysz, Dawid, Persing, John A., and Lifton, Richard P.
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CRANIOSYNOSTOSES ,GENETIC mutation ,WNT proteins ,RAS proteins ,CELLULAR signal transduction - Abstract
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10
-11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. [ABSTRACT FROM AUTHOR]- Published
- 2017
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28. A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury.
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Bixiao Zhao, Qiongshi Lu, Yuwei Cheng, Belcher, Justin M., Siew, Edward D., Leaf, David E., Body, Simon C., Fox, Amanda A., Waikar, Sushrut S., Collard, Charles D., Thiessen-Philbrook, Heather, Ikizler, T. Alp, Ware, Lorraine B., Edelstein, Charles L., Garg, Amit X., Murim Choi, Schaub, Jennifer A., Hongyu Zhao, Lifton, Richard P., and Parikh, Chirag R.
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ACUTE kidney failure ,APOLIPOPROTEINS ,CATASTROPHIC illness ,DISEASE susceptibility ,GENETIC polymorphisms ,CARDIAC surgery ,HIGH density lipoproteins ,INTENSIVE care units ,NONPARAMETRIC statistics ,PROTEINS ,RESEARCH funding ,SURGICAL complications ,CASE-control method ,SEQUENCE analysis ,GENOTYPES - Abstract
Rationale: Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed.Objectives: Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development.Methods: We conducted an exploratory genome-wide association study to identify single-nucleotide polymorphisms associated with genetic susceptibility to in-hospital acute kidney injury.Measurements and Main Results: We genotyped 609,508 single-nucleotide polymorphisms and performed genotype imputation in 760 acute kidney injury cases and 669 controls. We then evaluated polymorphisms that showed the strongest association with acute kidney injury in a replication patient population containing 206 cases with 1,406 controls. We observed an association between acute kidney injury and four single-nucleotide polymorphisms at two independent loci on metaanalysis of discovery and replication populations. These include rs62341639 (metaanalysis P = 2.48 × 10-7; odds ratio [OR], 0.64; 95% confidence interval [CI], 0.55-0.76) and rs62341657 (P = 3.26 × 10-7; OR, 0.65; 95% CI, 0.55-0.76) on chromosome 4 near APOL1-regulator IRF2, and rs9617814 (metaanalysis P = 3.81 × 10-6; OR, 0.70; 95% CI, 0.60-0.81) and rs10854554 (P = 6.53 × 10-7; OR, 0.67; 95% CI, 0.57-0.79) on chromosome 22 near acute kidney injury-related gene TBX1.Conclusions: Our findings reveal two genetic loci that are associated with acute kidney injury. Additional studies should be conducted to functionally evaluate these loci and to identify other common genetic variants contributing to acute kidney injury. [ABSTRACT FROM AUTHOR]- Published
- 2017
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29. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.
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Seidelmann, Sara B., Smith, Emily, Subrahmanyan, Lakshman, Dykas, Daniel, Abou Ziki, Maen D., Azari, Bani, Hannah-Shmouni, Fady, Yuexin Jiang, Akar, Joseph G., Marieb, Mark, Jacoby, Daniel, Bale, Allen E., Lifton, Richard P., and Mani, Arya
- Published
- 2017
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30. Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4.
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Arroyo, Juan Pablo, Junhui Zhang, Puthumana, Jeremy, Yarborough III, Orlando, Shigeru Shibata, Castañeda-Bueno, Maria, Lifton, Richard P., Rojas-Vega, Lorena, Gamba, Gerardo, and Rinehart, Jesse
- Subjects
PHYSIOLOGICAL effects of lysine ,PHOSPHORYLATION ,PROTEIN kinase C ,SODIUM-chloride cotransporter ,KIDNEY tubules ,RENIN-angiotensin system ,HYPERTENSION genetics ,BIOCHEMICAL genetics ,PHYSIOLOGY - Abstract
With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding. We tested whether these pathways also affect WNK4 phosphorylation and activity. By tandem mass spectrometry and use of phosphosite-specific antibodies, we identified five WNK4 sites (S47, S64, S1169, S1180, S1196) that are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332, which is required for kinase activation, and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule. Thus, AngII, in addition to increasing WNK4 levels, also modulates WNK4 kinase activity via phosphorylation of sites outside the kinase domain. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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31. PL-4: INSIGHTS INTO MOLECULAR MECHANISMS OF HYPERTENSION FROM HUMAN GENETICS.
- Author
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Lifton, Richard P.
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- 2023
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32. Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.
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Jiang, Tingting, Shi, Weiwei, Wali, Vikram B., Pongor, Lőrinc S., Li, Charles, Lau, Rosanna, Győrffy, Balázs, Lifton, Richard P., Symmans, William F., Pusztai, Lajos, and Hatzis, Christos
- Subjects
TRIPLE-negative breast cancer ,BREAST tumors ,ANTHRACYCLINES ,TAXANES ,CANCER chemotherapy ,ANTINEOPLASTIC agents ,HYDROCARBONS ,DRUG resistance in cancer cells ,GENOMES ,LONGITUDINAL method ,RESEARCH funding ,GENOMICS ,THERAPEUTICS - Abstract
Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.Methods and Findings: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.Conclusions: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. [ABSTRACT FROM AUTHOR]- Published
- 2016
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33. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.
- Author
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Falchetti, Marcella, Siming Zhao, Thakral, Durga, Jungmin Choi, Bi, Mark, Mane, Shrikant, Bilgüvar, Kaya, Lifton, Richard P., Edraki, Babak, Lee, Moses, Choi, Murim, Stiegler, Amy L., Boggon, Titus J., Schlessinger, Joseph, Birrer, Michael J., Kohn, Elise, Bellone, Stefania, Lopez, Salvatore, Schwab, Carlton, and English, Diana P.
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CARCINOSARCOMAS ,UTERINE cancer ,OVARIAN cancer ,EXONS (Genetics) ,EPITHELIAL cell culture - Abstract
Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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34. ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.
- Author
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Vilarinho, Sílvia, Sari, Sinan, Mazzacuva, Francesca, Bilgüvar, Kaya, Esendagli-Yilmaz, Güldal, Jain, Dhanpat, Akyol, Gülen, Dalgiç, Buket, Günel, Murat, Clayton, Peter T., Lifton, Richard P., Lee, Brendan H., and Valle, David
- Subjects
BILE acids ,PEROXISOMAL disorders ,LIVER diseases ,AMINOTRANSFERASES ,COGNITION disorders ,ATAXIA - Abstract
Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2. Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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35. Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.
- Author
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Rubinstein, Jill C., Brown, Taylor C., Christison-Lagay, Emily R., Yawei Zhang, Kunstman, John W., Juhlin, C. Christofer, Nelson-Williams, Carol, Goh, Gerald, Quinn, Courtney E., Callender, Glenda G., Udelsman, Robert, Lifton, Richard P., Korah, Reju, Carling, Tobias, and Zhang, Yawei
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THYROID cancer ,SOMATIC mutation ,PAPILLARY carcinoma ,CARCINOGENESIS ,NUCLEOTIDE sequencing ,EXOMES ,GENETIC polymorphisms ,GENETICS ,DISEASE risk factors ,AGE distribution ,CANCER ,GENOMES ,MOLECULAR structure ,RESEARCH funding ,THYROID gland tumors ,SEQUENCE analysis - Abstract
Background: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis.Methods: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples.Results: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden.Conclusions: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis. [ABSTRACT FROM AUTHOR]- Published
- 2016
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36. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.
- Author
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Vilarinho, Sílvia, Sari, Sinan, Yilmaz, Güldal, Stiegler, Amy L., Boggon, Titus J., Jain, Dhanpat, Akyol, Gulen, Dalgic, Buket, Günel, Murat, and Lifton, Richard P.
- Published
- 2016
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37. De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.
- Author
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Priest, James R., Osoegawa, Kazutoyo, Mohammed, Nebil, Nanda, Vivek, Kundu, Ramendra, Schultz, Kathleen, Lammer, Edward J., Girirajan, Santhosh, Scheetz, Todd, Waggott, Daryl, Haddad, Francois, Reddy, Sushma, Bernstein, Daniel, Burns, Trudy, Steimle, Jeffrey D., Yang, Xinan H., Moskowitz, Ivan P., Hurles, Matthew, Lifton, Richard P., and Nickerson, Debbie
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CONGENITAL heart disease ,ATRIOVENTRICULAR node ,ATRIAL septal defects ,VENTRICULAR septal defects ,LABORATORY mice - Abstract
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2
tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk. [ABSTRACT FROM AUTHOR]- Published
- 2016
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38. Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.
- Author
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Spier, Isabel, Drichel, Dmitriy, Kerick, Martin, Kirfel, Jutta, Horpaopan, Sukanya, Laner, Andreas, Holzapfel, Stefanie, Peters, Sophia, Adam, Ronja, Bixiao Zhao, Becker, Tim, Lifton, Richard P., Perner, Sven, Hoffmann, Per, Kristiansen, Glen, Timmermann, Bernd, Nöthen, Markus M., Holinski-Feder, Elke, Schweiger, Michal R., and Aretz, Stefan
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ADENOMATOUS polyposis coli ,MOSAICISM ,LEUCOCYTES ,SOMATIC mutation ,MOLECULAR genetics ,PATIENTS - Abstract
Background In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. Methods To comprehensively screen for somatic lowlevel APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ⩾2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. Results In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. Conclusions The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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39. Early and multiple origins of metastatic lineages within primary tumors.
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Zi-Ming Zhao, Bixiao Zhao, Yalai Bai, Iamarino, Atila, Gaffney, Stephen G., Schlessinger, Joseph, Lifton, Richard P., Rimm, David L., and Townsend, Jeffrey P.
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METASTASIS ,TUMOR treatment ,NEOPLASTIC cell transformation ,GENETIC mutation ,PHYLOGENY - Abstract
Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.
- Author
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Mark Bi, Siming Zhao, Said, Jonathan W., Merino, Maria J., Adeniran, Adebowale J., Zuoquan Xie, Nawaf, Cayce B., Jaehyuk Choi, Belldegrun, Arie S., Pantuck, Allan J., Klugeri, Harriet M., Bilgüvar, Kaya, Lifton, Richard P., and Shuch, Brian
- Subjects
RENAL cell carcinoma ,EXOMES ,NUCLEOTIDE sequencing ,SINGLE nucleotide polymorphisms ,HETEROZYGOSITY - Abstract
The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous- sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10
-4 ), increased frequency of nonsynonymous SSNVs in Pan- Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10-17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
41. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.
- Author
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Boyden, Lynn M., Kam, Chen Y., Hernández-Martín, Angela, Jing Zhou, Craiglow, Brittany G., Sidbury, Robert, Mathes, Erin F., Maguiness, Sheilagh M., Crumrine, Debra A., Williams, Mary L., Ronghua Hu, Lifton, Richard P., Elias, Peter M., Green, Kathleen J., and Choate, Keith A.
- Published
- 2016
- Full Text
- View/download PDF
42. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype.
- Author
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Scholl, Ute I., Healy, James M., Thiel, Anne, Fonseca, Annabelle L., Brown, Taylor C., Kunstman, John W., Horne, Matthew J., Dietrich, Dimo, Riemer, Jasmin, Kücükköylü, Seher, Reimer, Esther N., Reis, Anna‐Carinna, Goh, Gerald, Kristiansen, Glen, Mahajan, Amit, Korah, Reju, Lifton, Richard P., Prasad, Manju L., and Carling, Tobias
- Subjects
ADENOMA ,HYPERPLASIA ,CARDIOVASCULAR disease diagnosis ,HYPERTENSION ,COMPUTED tomography ,CELL analysis ,DIAGNOSIS - Abstract
Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs. Objective To characterize clinical--pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes. Design Retrospective study. Subjects and Measurements Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing. Results Mutation frequencies were as follows: KCNJ5, 37.1%; CACNA1D, 10.3%; ATP1A1, 8.2%; ATP2B3, 3.1%; and CTNNB1, 2.1%. Previously unidentified mutations included I157K, F154C and two insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0.007). On computed tomography, JCCiV/5-mutant tumours displayed significantly greater diameter (P = 0.023), calculated area (P = 0.002) and lower precontrast Hounsfleld units (P = 0.0002) vs tumours with mutations in other genes. Accordingly, JCCiV/5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 x 10 vs TIOTI-KCNJ5 mutant and P = 0.0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. Conclusions JCCiV/5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
43. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype.
- Author
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Perrault, Isabelle, Halbritter, Jan, Porath, Jonathan D., Gérard, Xavier, Braun, Daniela A., Heon Yung Gee, Fathy, Hanan M., Saunier, Sophie, Cormier-Daire, Valérie, Thomas, Sophie, Attié-Bitach, Tania, Boddaert, Nathalie, Taschner, Michael, Schueler, Markus, Lorentzen, Esben, Lifton, Richard P., Lawson, Jennifer A., Garfa-Traore, Meriem, Otto, Edgar A., and Bastin, Philippe
- Subjects
CILIOPATHY ,ETIOLOGY of diseases ,CARRIER proteins ,GENETIC mutation ,POLYDACTYLY ,NEURONAL ceroid-lipofuscinosis ,RETINAL degeneration ,FIBROBLASTS - Abstract
Background Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods We screened 1628 individuals with renoocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
44. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
- Author
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Lifton, Richard P, Cheng, Elaine, Halaban, Ruth, McCusker, James P, Ma, Shuangge, Sznol, Mario, Krauthammer, Michael, Serin, Merdan, Evans, Perry, Mane, Shrikant, Bacchiocchi, Antonella, Pornputtapong, Natapol, Narayan, Deepak, Kluger, Harriet M, Bosenberg, Marcus, Kong, Yong, Wu, Cen, Ariyan, Stephan, Schlessinger, Joseph, and Straub, Robert
- Subjects
MELANOMA ,NEUROFIBROMIN ,RAS oncogenes ,BRAF genes ,GUANOSINE triphosphatase - Abstract
We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
45. Genomic landscape of cutaneous T cell lymphoma.
- Author
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Choi, Jaehyuk, Maman, Yaakov, Walradt, Trent, Wang, Tiffany, Subtil, Antonio, Edelson, Richard L, Barbarotta, Lisa, Boggon, Titus J, Goh, Gerald, Tordoff, Jesse, Devine, Lesley, Lifton, Richard P, Hong, Bok S, Liu, Kristina J, Lewis, Julia M, Chen, Kan, Carlson, Kacie, Foss, Francine M, Overton, John D, and Schatz, David G
- Subjects
CUTANEOUS T-cell lymphoma ,HUMAN carcinogenesis ,APOPTOSIS ,NF-kappa B ,HUMAN chromatin - Abstract
Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs versus 1.0 somatic single-nucleotide variant per CTCL). These findings have implications for new therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
46. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2 D as a recurrently mutated gene.
- Author
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Juhlin, C. Christofer, Stenman, Adam, Haglund, Felix, Clark, Victoria E., Brown, Taylor C., Baranoski, Jacob, Bilguvar, Kaya, Goh, Gerald, Welander, Jenny, Svahn, Fredrika, Rubinstein, Jill C., Caramuta, Stefano, Yasuno, Katsuhito, Günel, Murat, Bäckdahl, Martin, Gimm, Oliver, Söderkvist, Peter, Prasad, Manju L., Korah, Reju, and Lifton, Richard P.
- Published
- 2015
- Full Text
- View/download PDF
47. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.
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Spier, Isabel, Holzapfel, Stefanie, Altmüller, Janine, Zhao, Bixiao, Horpaopan, Sukanya, Vogt, Stefanie, Chen, Sophia, Morak, Monika, Raeder, Susanne, Kayser, Katrin, Stienen, Dietlinde, Adam, Ronja, Nürnberg, Peter, Plotz, Guido, Holinski‐Feder, Elke, Lifton, Richard P., Thiele, Holger, Hoffmann, Per, Steinke, Verena, and Aretz, Stefan
- Abstract
In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
48. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing.
- Author
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Kunstman, John W., Juhlin, C. Christofer, Goh, Gerald, Brown, Taylor C., Stenman, Adam, Healy, James M., Rubinstein, Jill C., Choi, Murim, Kiss, Nimrod, Nelson-Williams, Carol, Mane, Shrikant, Rimm, David L., Prasad, Manju L., Höög, Anders, Zedenius, Jan, Larsson, Catharina, Korah, Reju, Lifton, Richard P., and Carling, Tobias
- Published
- 2015
- Full Text
- View/download PDF
49. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.
- Author
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Nelson-Williams, Carol, Vichot, Alfred A., Goh, Gerald, Scholl, Ute I., Choi, Murim, Loring, Erin, Lifton, Richard P., Rasoulpour, Majid, Bowlin, David L., Sethna, Christine B., Trachtman, Howard, Quack, Ivo, Rump, Lars C., Thiel, Anne, Stölting, Gabriel, Fahlke, Christoph, Prasad, Manju L., Carling, Tobias, Juhlin, C. Christofer, and Lande, Marc
- Subjects
GENETIC mutation ,HYPERTENSION ,HYPERALDOSTERONISM ,INTRACELLULAR calcium ,PHENOTYPES - Published
- 2015
- Full Text
- View/download PDF
50. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation.
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Shibata, Shigeru, Arroyo, Juan Pablo, Castañeda-Bueno, María, Puthumana, Jeremy, Junhui Zhang, Shunya Uchida, Stone, Kathryn L., Lam, TuKiet T., and Lifton, Richard P.
- Subjects
PROTEIN kinase C ,HYPERTENSION ,CARDIOVASCULAR diseases ,HYPERKALEMIA ,UBIQUITIN ligases ,PHOSPHORYLATION - Abstract
Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K
+ reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K+ secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)—components of an E3 ubiquitin ligase complex that targets WNKs for degradation—cause constitutively increased renal salt reabsorption and impaired K+ secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3S433 phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K+ secretion in the setting of volume depletion. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
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