A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region
Abstract Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting i...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
|
| Series: | eJHaem |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jha2.165 |
| _version_ | 1828716030441029632 |
|---|---|
| author | Jonathan W. Arthur Hilda A. Pickett Pasquale M. Barbaro Tatjana Kilo Raja S. Vasireddy Traude H. Beilharz David R. Powell Emma L. Hackett Bruce Bennetts Julie A. Curtin Kristi Jones John Christodoulou Roger R. Reddel Juliana Teo Tracy M. Bryan |
| author_facet | Jonathan W. Arthur Hilda A. Pickett Pasquale M. Barbaro Tatjana Kilo Raja S. Vasireddy Traude H. Beilharz David R. Powell Emma L. Hackett Bruce Bennetts Julie A. Curtin Kristi Jones John Christodoulou Roger R. Reddel Juliana Teo Tracy M. Bryan |
| author_sort | Jonathan W. Arthur |
| collection | DOAJ |
| description | Abstract Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30‐40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease‐causing genes. Here we describe a family in which a partial deletion of the 3′ untranslated region (3′ UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3′ UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3′ UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease. |
| first_indexed | 2024-03-12T14:06:29Z |
| format | Article |
| id | doaj.art-36c1fe6971a84a47afc842d5b03c9c42 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-03-12T14:06:29Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-36c1fe6971a84a47afc842d5b03c9c422023-08-21T14:06:07ZengWileyeJHaem2688-61462021-05-012215716610.1002/jha2.165A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated regionJonathan W. Arthur0Hilda A. Pickett1Pasquale M. Barbaro2Tatjana Kilo3Raja S. Vasireddy4Traude H. Beilharz5David R. Powell6Emma L. Hackett7Bruce Bennetts8Julie A. Curtin9Kristi Jones10John Christodoulou11Roger R. Reddel12Juliana Teo13Tracy M. Bryan14Children's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales AustraliaChildren's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales AustraliaChildren's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales AustraliaHaematology Department Children's Hospital at Westmead Westmead New South Wales AustraliaHaematology Department Children's Hospital at Westmead Westmead New South Wales AustraliaMonash Biomedicine Discovery Institute Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria AustraliaMonash Bioinformatics Platform Monash University Clayton Victoria AustraliaDepartment of Molecular Genetics Children's Hospital Westmead Westmead New South Wales AustraliaDepartment of Molecular Genetics Children's Hospital Westmead Westmead New South Wales AustraliaHaematology Department Children's Hospital at Westmead Westmead New South Wales AustraliaDisciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and Health University of Sydney Westmead New South Wales AustraliaDisciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and Health University of Sydney Westmead New South Wales AustraliaChildren's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales AustraliaHaematology Department Children's Hospital at Westmead Westmead New South Wales AustraliaChildren's Medical Research Institute Faculty of Medicine and Health, University of Sydney Westmead New South Wales AustraliaAbstract Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30‐40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease‐causing genes. Here we describe a family in which a partial deletion of the 3′ untranslated region (3′ UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3′ UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3′ UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.https://doi.org/10.1002/jha2.165DKC1dyskeratosis congenitapolyadenylationtelomerasetelomeres |
| spellingShingle | Jonathan W. Arthur Hilda A. Pickett Pasquale M. Barbaro Tatjana Kilo Raja S. Vasireddy Traude H. Beilharz David R. Powell Emma L. Hackett Bruce Bennetts Julie A. Curtin Kristi Jones John Christodoulou Roger R. Reddel Juliana Teo Tracy M. Bryan A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region eJHaem DKC1 dyskeratosis congenita polyadenylation telomerase telomeres |
| title | A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region |
| title_full | A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region |
| title_fullStr | A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region |
| title_full_unstemmed | A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region |
| title_short | A novel cause of DKC1‐related bone marrow failure: Partial deletion of the 3′ untranslated region |
| title_sort | novel cause of dkc1 related bone marrow failure partial deletion of the 3 untranslated region |
| topic | DKC1 dyskeratosis congenita polyadenylation telomerase telomeres |
| url | https://doi.org/10.1002/jha2.165 |
| work_keys_str_mv | AT jonathanwarthur anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT hildaapickett anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT pasqualembarbaro anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT tatjanakilo anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT rajasvasireddy anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT traudehbeilharz anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT davidrpowell anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT emmalhackett anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT brucebennetts anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT julieacurtin anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT kristijones anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT johnchristodoulou anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT rogerrreddel anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT julianateo anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT tracymbryan anovelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT jonathanwarthur novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT hildaapickett novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT pasqualembarbaro novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT tatjanakilo novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT rajasvasireddy novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT traudehbeilharz novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT davidrpowell novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT emmalhackett novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT brucebennetts novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT julieacurtin novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT kristijones novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT johnchristodoulou novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT rogerrreddel novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT julianateo novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion AT tracymbryan novelcauseofdkc1relatedbonemarrowfailurepartialdeletionofthe3untranslatedregion |