A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation
Abstract Background Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-07-01
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| Series: | Genome Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13059-017-1274-3 |
| _version_ | 1818991928961662976 |
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| author | Nisha Patel Arif O. Khan Maher Al-Saif Walid N. Moghrabi Balsam M. AlMaarik Niema Ibrahim Firdous Abdulwahab Mais Hashem Tarfa Alshidi Eman Alobeid Rana A. Alomar Saad Al-Harbi Mohamed Abouelhoda Khalid S. A. Khabar Fowzan S. Alkuraya |
| author_facet | Nisha Patel Arif O. Khan Maher Al-Saif Walid N. Moghrabi Balsam M. AlMaarik Niema Ibrahim Firdous Abdulwahab Mais Hashem Tarfa Alshidi Eman Alobeid Rana A. Alomar Saad Al-Harbi Mohamed Abouelhoda Khalid S. A. Khabar Fowzan S. Alkuraya |
| author_sort | Nisha Patel |
| collection | DOAJ |
| description | Abstract Background Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic. Results We report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3′ UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3′ UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein. Conclusions This novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3′ UTR mutations with tissue-specific pathology. |
| first_indexed | 2024-12-20T20:18:04Z |
| format | Article |
| id | doaj.art-1b2694375998473488e8741b9e6ca008 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-20T20:18:04Z |
| publishDate | 2017-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-1b2694375998473488e8741b9e6ca0082022-12-21T19:27:39ZengBMCGenome Biology1474-760X2017-07-0118111010.1186/s13059-017-1274-3A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutationNisha Patel0Arif O. Khan1Maher Al-Saif2Walid N. Moghrabi3Balsam M. AlMaarik4Niema Ibrahim5Firdous Abdulwahab6Mais Hashem7Tarfa Alshidi8Eman Alobeid9Rana A. Alomar10Saad Al-Harbi11Mohamed Abouelhoda12Khalid S. A. Khabar13Fowzan S. Alkuraya14Department of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterProgram in BioMolecular Research, King Faisal Specialist Hospital and Research CenterProgram in BioMolecular Research, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterKing Khaled Eye Specialist HospitalDepartment of Genetics, King Faisal Specialist Hospital and Research CenterProgram in BioMolecular Research, King Faisal Specialist Hospital and Research CenterDepartment of Genetics, King Faisal Specialist Hospital and Research CenterAbstract Background Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic. Results We report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3′ UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3′ UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein. Conclusions This novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3′ UTR mutations with tissue-specific pathology.http://link.springer.com/article/10.1186/s13059-017-1274-3AU-rich elementsVariable expressivityTissue-specificCornea3′UTR |
| spellingShingle | Nisha Patel Arif O. Khan Maher Al-Saif Walid N. Moghrabi Balsam M. AlMaarik Niema Ibrahim Firdous Abdulwahab Mais Hashem Tarfa Alshidi Eman Alobeid Rana A. Alomar Saad Al-Harbi Mohamed Abouelhoda Khalid S. A. Khabar Fowzan S. Alkuraya A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation Genome Biology AU-rich elements Variable expressivity Tissue-specific Cornea 3′UTR |
| title | A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation |
| title_full | A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation |
| title_fullStr | A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation |
| title_full_unstemmed | A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation |
| title_short | A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation |
| title_sort | novel mechanism for variable phenotypic expressivity in mendelian diseases uncovered by an au rich element are creating mutation |
| topic | AU-rich elements Variable expressivity Tissue-specific Cornea 3′UTR |
| url | http://link.springer.com/article/10.1186/s13059-017-1274-3 |
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