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Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-4185-7409
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6452-2199
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. University of Presov.
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2015 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 12, 1679-1683 p.Article in journal (Refereed) Published
Abstract [en]

Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin γ-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

Place, publisher, year, edition, pages
2015. Vol. 23, no 12, 1679-1683 p.
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-244419DOI: 10.1038/ejhg.2015.49ISI: 000365129700015PubMedID: 25782675OAI: oai:DiVA.org:uu-244419DiVA: diva2:792381
Funder
Swedish Research Council, K2013-66X-10829-20-3
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2015-03-03 Created: 2015-02-16 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Genetics of Two Mendelian Traits and Validation of Induced Pluripotent Stem Cell (iPSC) Technology for Disease Modeling
Open this publication in new window or tab >>Genetics of Two Mendelian Traits and Validation of Induced Pluripotent Stem Cell (iPSC) Technology for Disease Modeling
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Novel technologies for genome analysis have provided almost unlimited opportunities to uncover structural gene variants behind human disorders. Whole exome sequencing (WES) is especially useful for understanding rare Mendelian conditions, because it reduces the requirements for a priori clinical data, and can be applied on a small number of patients. However, supporting functional data on the effect of specific gene variants are often required to power these findings. A variety of methods and biological model systems exists for this purpose. Among those, induced pluripotent stem cells (iPSCs), which are capable of self-renewal and differentiation, stand out as an alternative to animal models.

In papers I and II we took advantage of WES to identify gene variants underlying autosomal recessive pure hair and nail ectodermal dysplasia (AR PHNED) as well as autosomal dominant familial visceral myopathy (FVM). We identified a homozygous variant c.821T>C (p.Phe274Ser) in the KRT74 gene as the causative mutation in AR PHNED, supported by the fact that Keratin-74 was undetectable in hair follicles of an affected family member. In a family segregating FVM we found a heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in the ACTG2 gene in the affected members. This novel variant is associated with a broad range of visceral symptoms and a variable age of onset.

In Paper III we explored the similarity between clonally derived iPSC lines originating from a single parental fibroblast line and we highlighted the necessity to use lines originating from various donors in disease modeling because of biological variation. Paper IV focused on how the genomic integrity of iPSCs is affected by the choice of reprogramming methods. We described several novel cytogenetic rearrangements in iPSCs and we identified a chromosome 5q duplication as a candidate aberration for growth advantage.

In summary, this doctoral thesis brings novel findings on unreported disease-causing variants, as supported by extensive genetic analysis and functional data. A novel molecular mechanism behind AR PHNED is presented and the phenotypic spectrum associated with FVM is expanded. In addition, the thesis brings novel understanding of benefits and limitations of the iPSC technology to be considered for disease modeling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1078
Keyword
Disease modeling, Mendelian disorders, iPSC, Whole exome sequencing, Transcriptome sequencing
National Category
Genetics Cell Biology Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-246228 (URN)978-91-554-9184-0 (ISBN)
Public defence
2015-04-24, Fåhraeussalen, Rudbeck Laboratoriet, Dag Hammarsjöldsväg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-04-01 Created: 2015-03-03 Last updated: 2015-09-24

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Klar, JoakimRaykova, DoroteyaGustafson, ElisabetAmeur, AdamWanders, AlkwinDahl, Niklas

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Klar, JoakimRaykova, DoroteyaGustafson, ElisabetAmeur, AdamWanders, AlkwinDahl, Niklas
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLabPaediatric SurgeryDepartment of Immunology, Genetics and PathologyMolecular and Morphological Pathology
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