Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome
The <i>LMNA</i> gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in <i>LMNA</i> cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants...
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MDPI AG
2024-01-01
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| Online Access: | https://www.mdpi.com/2073-4425/15/1/112 |
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| author | Matheus V. M. B. Wilke Myra Wick Tanya L. Schwab Rodrigo Tzovenos Starosta Karl J. Clark Heidi M. Connolly Eric W. Klee |
| author_facet | Matheus V. M. B. Wilke Myra Wick Tanya L. Schwab Rodrigo Tzovenos Starosta Karl J. Clark Heidi M. Connolly Eric W. Klee |
| author_sort | Matheus V. M. B. Wilke |
| collection | DOAJ |
| description | The <i>LMNA</i> gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in <i>LMNA</i> cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for <i>LMNA</i>-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an <i>LMNA</i> variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (<i>p</i> < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family. |
| first_indexed | 2024-03-08T10:52:31Z |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-08T10:52:31Z |
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| spelling | doaj.art-abca124dcf40408c9f802a9a16d0671d2024-01-26T16:43:39ZengMDPI AGGenes2073-44252024-01-0115111210.3390/genes15010112Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria SyndromeMatheus V. M. B. Wilke0Myra Wick1Tanya L. Schwab2Rodrigo Tzovenos Starosta3Karl J. Clark4Heidi M. Connolly5Eric W. Klee6Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USADepartment of Molecular Hematology, Mayo Clinic, Rochester, MN 55905, USADivision of Medical Genetics and Genomics, Washington University in Saint Louis, Saint Louis, MO 63130, USADepartment of Biochemical and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USADepartment of Cardiology, Mayo Clinic, Rochester, MN 55905, USACenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USAThe <i>LMNA</i> gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in <i>LMNA</i> cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for <i>LMNA</i>-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an <i>LMNA</i> variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (<i>p</i> < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.https://www.mdpi.com/2073-4425/15/1/112atypical progeroid syndrome<i>LMNA</i>mitral valve calcificationnuclear abnormalitiescase report |
| spellingShingle | Matheus V. M. B. Wilke Myra Wick Tanya L. Schwab Rodrigo Tzovenos Starosta Karl J. Clark Heidi M. Connolly Eric W. Klee Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome Genes atypical progeroid syndrome <i>LMNA</i> mitral valve calcification nuclear abnormalities case report |
| title | Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome |
| title_full | Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome |
| title_fullStr | Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome |
| title_full_unstemmed | Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome |
| title_short | Nuclear Abnormalities in <i>LMNA</i> p.(Glu2Lys) Variant Segregating with <i>LMNA</i>-Associated Cardiocutaneous Progeria Syndrome |
| title_sort | nuclear abnormalities in i lmna i p glu2lys variant segregating with i lmna i associated cardiocutaneous progeria syndrome |
| topic | atypical progeroid syndrome <i>LMNA</i> mitral valve calcification nuclear abnormalities case report |
| url | https://www.mdpi.com/2073-4425/15/1/112 |
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