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      Heterozygous De Novo and Inherited Mutations in the Smooth Muscle Actin ( ACTG2) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

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          Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

          Author Summary

          In 1976, a radiologist, Walter Berdon described a group of patients with a rare intestinal and bladder disorder in which the smooth muscle of those organs failed to contract. These patients are unable to digest food, require multiple abdominal surgeries and are diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Since the description of MMIHS, the genes that cause it have remained a mystery. We followed and obtained DNA from patients with this disorder over a period of over 14 years and assembled a large group of cases. We used whole-exome sequencing, a powerful tool used to identify disease genes, and found mutations in ACTG2, a visceral actin gene. Actins are components of muscle contractile units, and one Finnish family has been previously found with less severe gastrointestinal problems due to mutations in this gene. In our patients, we find de novo mutations in the majority of cases of MMIHS. However, we also find families with the disease over several generations due to these same mutations. This work provides the first disease gene for MMIHS, and suggests new treatment options.

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          Most cited references 46

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          DNASTAR's Lasergene sequence analysis software.

           T G Burland (1999)
          Lasergene's eight modules provide tools that enable users to accomplish each step of sequence analysis, from trimming and assembly of sequence data, to gene discovery, annotation, gene product analysis, sequence similarity searches, sequence alignment, phylogenetic analysis, oligonucleotide primer design, cloning strategies, and publication of the results. The Lasergene software suite provides the functions and customization tools needed so that users can perform analyses the software writers never imagined.
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            An integrative variant analysis suite for whole exome next-generation sequencing data

            Background Whole exome capture sequencing allows researchers to cost-effectively sequence the coding regions of the genome. Although the exome capture sequencing methods have become routine and well established, there is currently a lack of tools specialized for variant calling in this type of data. Results Using statistical models trained on validated whole-exome capture sequencing data, the Atlas2 Suite is an integrative variant analysis pipeline optimized for variant discovery on all three of the widely used next generation sequencing platforms (SOLiD, Illumina, and Roche 454). The suite employs logistic regression models in conjunction with user-adjustable cutoffs to accurately separate true SNPs and INDELs from sequencing and mapping errors with high sensitivity (96.7%). Conclusion We have implemented the Atlas2 Suite and applied it to 92 whole exome samples from the 1000 Genomes Project. The Atlas2 Suite is available for download at In addition to a command line version, the suite has been integrated into the Genboree Workbench, allowing biomedical scientists with minimal informatics expertise to remotely call, view, and further analyze variants through a simple web interface. The existing genomic databases displayed via the Genboree browser also streamline the process from variant discovery to functional genomics analysis, resulting in an off-the-shelf toolkit for the broader community.
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              Cellular and molecular mechanisms underlying muscular dystrophy

              The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                March 2014
                27 March 2014
                : 10
                : 3
                [1 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
                [2 ]Texas Children's Hospital, Houston, Texas, United States of America
                [3 ]Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland
                [4 ]Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
                [5 ]Children's Clinical University Hospital, Riga, Latvia
                [6 ]Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
                [7 ]Department of Genetics, Children's Hospital Colorado, Aurora, Colorado
                [8 ]Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America
                Stanford University School of Medicine, United States of America
                Author notes

                The authors have read the journal's policy and have the following conflicts: The Department of Molecular and Human Genetics at Baylor College of Medicine (BCM) offers extensive genetic laboratory testing, and BCM derives revenue from this activity. The Department offers chromosomal microarray analysis, whole-exome sequencing, and many other tests.

                Conceived and designed the experiments: AB MFW DB TM ELL RAG JRL. Performed the experiments: CGJ MFW TM FX YY SJ DMM. Analyzed the data: MFW CGJ TG FX YY JB. Contributed reagents/materials/analysis tools: AC FJP SW IE LK CAB DB JN AL SP. Wrote the paper: MFW CGJ TG RAG JRL AB.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 11
                This work was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS058529 to JRL and the National Human Genome Research Institute (NHGRI) Baylor Hopkins Center for Mendelian Genomics grant U54 HG006542. MFW received funding from the NINDS (NS076547), and the Simmons Family Foundation. FJP holds a Career Award for Medical Scientists (CAMS) from the Burroughs-Wellcome Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Medicine and Health Sciences
                Clinical Genetics
                Gastroenterology and Hepatology
                Gastrointestinal Motility Disorders
                Pediatric Gastroenterology



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