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Genetics

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Genomic imbalances in pediatric patients with chronic kidney disease
Miguel Verbitsky, … , Craig S. Wong, Ali G. Gharavi
Miguel Verbitsky, … , Craig S. Wong, Ali G. Gharavi
Published April 20, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI80877.
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Genomic imbalances in pediatric patients with chronic kidney disease

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Abstract

BACKGROUND. There is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown.

METHODS. We performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD.

RESULTS. We identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeobox B (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 × 10–20). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease.

CONCLUSION. A substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00327860.

FUNDING. This work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.

Authors

Miguel Verbitsky, Simone Sanna-Cherchi, David A. Fasel, Brynn Levy, Krzysztof Kiryluk, Matthias Wuttke, Alison G. Abraham, Frederick Kaskel, Anna Köttgen, Bradley A. Warady, Susan L. Furth, Craig S. Wong, Ali G. Gharavi

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Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model
Sara Silva-Santos, … , Steven A. Kushner, Ype Elgersma
Sara Silva-Santos, … , Steven A. Kushner, Ype Elgersma
Published April 13, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI80554.
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Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

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Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.

Authors

Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel, Steven A. Kushner, Ype Elgersma

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TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts
Diana L. Bernstein, … , Elena G. Ruano, Klaus H. Kaestner
Diana L. Bernstein, … , Elena G. Ruano, Klaus H. Kaestner
Published April 13, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI77321.
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TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts

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Abstract

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator–like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics.

Authors

Diana L. Bernstein, John E. Le Lay, Elena G. Ruano, Klaus H. Kaestner

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NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Published March 23, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI79735.
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NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

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Abstract

Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage.

Authors

Wenjun Xiong, Alexandra E. MacColl Garfinkel, Yiqing Li, Larry I. Benowitz, Constance L. Cepko

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Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice
Aditya Venkatesh, … , Markus A. Rüegg, Claudio Punzo
Aditya Venkatesh, … , Markus A. Rüegg, Claudio Punzo
Published March 23, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI79766.
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Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

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Abstract

Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.

Authors

Aditya Venkatesh, Shan Ma, Yun Z. Le, Michael N. Hall, Markus A. Rüegg, Claudio Punzo

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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
Joshua W. Knowles, … , Mark Walker, Thomas Quertermous
Joshua W. Knowles, … , Mark Walker, Thomas Quertermous
Published March 23, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI74692.
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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

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Abstract

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 “A” allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

Authors

Joshua W. Knowles, Weijia Xie, Zhongyang Zhang, Indumathi Chennemsetty, Themistocles L. Assimes, Jussi Paananen, Ola Hansson, James Pankow, Mark O. Goodarzi, Ivan Carcamo-Orive, Andrew P. Morris, Yii-Der I. Chen, Ville-Petteri Mäkinen, Andrea Ganna, Anubha Mahajan, Xiuqing Guo, Fahim Abbasi, Danielle M. Greenawalt, Pek Lum, Cliona Molony, Lars Lind, Cecilia Lindgren, Leslie J. Raffel, Philip S. Tsao, Eric E. Schadt, Jerome I. Rotter, Alan Sinaiko, Gerald Reaven, Xia Yang, Chao A. Hsiung, Leif Groop, Heather J. Cordell, Markku Laakso, Ke Hao, Erik Ingelsson, Timothy M. Frayling, Michael N. Weedon, Mark Walker, Thomas Quertermous

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Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti
Keith A. Choate, … , Leonard M. Milstone, Richard P. Lifton
Keith A. Choate, … , Leonard M. Milstone, Richard P. Lifton
Published March 16, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI64415.
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Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

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Abstract

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

Authors

Keith A. Choate, Yin Lu, Jing Zhou, Peter M. Elias, Samir Zaidi, Amy S. Paller, Anita Farhi, Carol Nelson-Williams, Debra Crumrine, Leonard M. Milstone, Richard P. Lifton

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Functional variants of POC5 identified in patients with idiopathic scoliosis
Shunmoogum A. Patten, … , Florina Moldovan, Patrick Edery
Shunmoogum A. Patten, … , Florina Moldovan, Patrick Edery
Published February 2, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI77262.
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Functional variants of POC5 identified in patients with idiopathic scoliosis

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Abstract

Idiopathic scoliosis (IS) is a spine deformity that affects approximately 3% of the population. The underlying causes of IS are not well understood, although there is clear evidence that there is a genetic component to the disease. Genetic mapping studies suggest high genetic heterogeneity, but no IS disease-causing gene has yet been identified. Here, genetic linkage analyses combined with exome sequencing identified a rare missense variant (p.A446T) in the centriolar protein gene POC5 that cosegregated with the disease in a large family with multiple members affected with IS. Subsequently, the p.A446T variant was found in an additional set of families with IS and in an additional 3 cases of IS. Moreover, POC5 variant p.A455P was present and linked to IS in one family and another rare POC5 variant (p.A429V) was identified in an additional 5 cases of IS. In a zebrafish model, expression of any of the 3 human IS-associated POC5 variant mRNAs resulted in spine deformity, without affecting other skeletal structures. Together, these findings indicate that mutations in the POC5 gene contribute to the occurrence of IS.

Authors

Shunmoogum A. Patten, Patricia Margaritte-Jeannin, Jean-Claude Bernard, Eudeline Alix, Audrey Labalme, Alicia Besson, Simon L. Girard, Khaled Fendri, Nicolas Fraisse, Bernard Biot, Coline Poizat, Amandine Campan-Fournier, Kariman Abelin-Genevois, Vincent Cunin, Charlotte Zaouter, Meijiang Liao, Raphaelle Lamy, Gaetan Lesca, Rita Menassa, Charles Marcaillou, Melanie Letexier, Damien Sanlaville, Jerome Berard, Guy A. Rouleau, Françoise Clerget-Darpoux, Pierre Drapeau, Florina Moldovan, Patrick Edery

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Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes
Bo Yuan, … , Richard A. Gibbs, James R. Lupski
Bo Yuan, … , Richard A. Gibbs, James R. Lupski
Published January 9, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI77435.
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Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

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Abstract

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be “transcriptomopathies” rather than cohesinopathies.

Authors

Bo Yuan, Davut Pehlivan, Ender Karaca, Nisha Patel, Wu-Lin Charng, Tomasz Gambin, Claudia Gonzaga-Jauregui, V. Reid Sutton, Gozde Yesil, Sevcan Tug Bozdogan, Tulay Tos, Asuman Koparir, Erkan Koparir, Christine R. Beck, Shen Gu, Huseyin Aslan, Ozge Ozalp Yuregir, Khalid Al Rubeaan, Dhekra Alnaqeb, Muneera J. Alshammari, Yavuz Bayram, Mehmed M. Atik, Hatip Aydin, B. Bilge Geckinli, Mehmet Seven, Hakan Ulucan, Elif Fenercioglu, Mustafa Ozen, Shalini Jhangiani, Donna M. Muzny, Eric Boerwinkle, Beyhan Tuysuz, Fowzan S. Alkuraya, Richard A. Gibbs, James R. Lupski

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Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability
Saleh AlAsiri, … , Michael A. Trakselis, Aleksandar Rajkovic
Saleh AlAsiri, … , Michael A. Trakselis, Aleksandar Rajkovic
Published December 1, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI78473.
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Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability

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Abstract

Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability.

Authors

Saleh AlAsiri, Sulman Basit, Michelle A. Wood-Trageser, Svetlana A. Yatsenko, Elizabeth P. Jeffries, Urvashi Surti, Deborah M. Ketterer, Sibtain Afzal, Khushnooda Ramzan, Muhammad Faiyaz-Ul Haque, Huaiyang Jiang, Michael A. Trakselis, Aleksandar Rajkovic

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A hop, exon skip, and a jump for muscular dystrophy
Quan Gao and colleagues developed an exon skipping strategy that generates a truncated, functional γ-sarcoglycan protein and improves defects in muscular dystrophy models…
Published October 12, 2015
Scientific Show StopperGenetics

A curve in the spine
Shunmoogum Patten and colleagues identify variants of POC5 that are associated with idiopathic scoliosis…
Published February 2, 2015
Scientific Show StopperGenetics
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