Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.
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 rema...
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Public Library of Science (PLoS)
2014-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004258&type=printable |
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| author | Michael F Wangler Claudia Gonzaga-Jauregui Tomasz Gambin Samantha Penney Timothy Moss Atul Chopra Frank J Probst Fan Xia Yaping Yang Steven Werlin Ieva Eglite Liene Kornejeva Carlos A Bacino Dustin Baldridge Jeff Neul Efrat Lev Lehman Austin Larson Joke Beuten Donna M Muzny Shalini Jhangiani Baylor-Hopkins Center for Mendelian Genomics Richard A Gibbs James R Lupski Arthur Beaudet |
| author_facet | Michael F Wangler Claudia Gonzaga-Jauregui Tomasz Gambin Samantha Penney Timothy Moss Atul Chopra Frank J Probst Fan Xia Yaping Yang Steven Werlin Ieva Eglite Liene Kornejeva Carlos A Bacino Dustin Baldridge Jeff Neul Efrat Lev Lehman Austin Larson Joke Beuten Donna M Muzny Shalini Jhangiani Baylor-Hopkins Center for Mendelian Genomics Richard A Gibbs James R Lupski Arthur Beaudet |
| author_sort | Michael F Wangler |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5e906b4e11814a4b99a07d1ad5eeb99e |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2014-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-5e906b4e11814a4b99a07d1ad5eeb99e2025-08-20T02:15:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-03-01103e100425810.1371/journal.pgen.1004258Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.Michael F WanglerClaudia Gonzaga-JaureguiTomasz GambinSamantha PenneyTimothy MossAtul ChopraFrank J ProbstFan XiaYaping YangSteven WerlinIeva EgliteLiene KornejevaCarlos A BacinoDustin BaldridgeJeff NeulEfrat Lev LehmanAustin LarsonJoke BeutenDonna M MuznyShalini JhangianiBaylor-Hopkins Center for Mendelian GenomicsRichard A GibbsJames R LupskiArthur BeaudetMegacystis-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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004258&type=printable |
| spellingShingle | Michael F Wangler Claudia Gonzaga-Jauregui Tomasz Gambin Samantha Penney Timothy Moss Atul Chopra Frank J Probst Fan Xia Yaping Yang Steven Werlin Ieva Eglite Liene Kornejeva Carlos A Bacino Dustin Baldridge Jeff Neul Efrat Lev Lehman Austin Larson Joke Beuten Donna M Muzny Shalini Jhangiani Baylor-Hopkins Center for Mendelian Genomics Richard A Gibbs James R Lupski Arthur Beaudet Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genetics |
| title | Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. |
| title_full | Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. |
| title_fullStr | Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. |
| title_full_unstemmed | Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. |
| title_short | Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. |
| title_sort | heterozygous de novo and inherited mutations in the smooth muscle actin actg2 gene underlie megacystis microcolon intestinal hypoperistalsis syndrome |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004258&type=printable |
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