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CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures

BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis...

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Autores principales: Sargolzaeiaval, Forough, Zhang, Jiaming, Schleit, Jennifer, Lessel, Davor, Kubisch, Christian, Precioso, Debora R., Sillence, David, Hisama, Fuki M., Dorschner, Michael, Martin, George M., Oshima, Junko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305643/
https://www.ncbi.nlm.nih.gov/pubmed/30393977
http://dx.doi.org/10.1002/mgg3.495
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author Sargolzaeiaval, Forough
Zhang, Jiaming
Schleit, Jennifer
Lessel, Davor
Kubisch, Christian
Precioso, Debora R.
Sillence, David
Hisama, Fuki M.
Dorschner, Michael
Martin, George M.
Oshima, Junko
author_facet Sargolzaeiaval, Forough
Zhang, Jiaming
Schleit, Jennifer
Lessel, Davor
Kubisch, Christian
Precioso, Debora R.
Sillence, David
Hisama, Fuki M.
Dorschner, Michael
Martin, George M.
Oshima, Junko
author_sort Sargolzaeiaval, Forough
collection PubMed
description BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication. METHODS: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes. RESULTS: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non‐telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC‐rich sequences. CONCLUSION: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra‐familial variations of CRMCC.
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spelling pubmed-63056432019-01-02 CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures Sargolzaeiaval, Forough Zhang, Jiaming Schleit, Jennifer Lessel, Davor Kubisch, Christian Precioso, Debora R. Sillence, David Hisama, Fuki M. Dorschner, Michael Martin, George M. Oshima, Junko Mol Genet Genomic Med Original Articles BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication. METHODS: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes. RESULTS: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non‐telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC‐rich sequences. CONCLUSION: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra‐familial variations of CRMCC. John Wiley and Sons Inc. 2018-11-04 /pmc/articles/PMC6305643/ /pubmed/30393977 http://dx.doi.org/10.1002/mgg3.495 Text en © 2018 University of Washington. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Sargolzaeiaval, Forough
Zhang, Jiaming
Schleit, Jennifer
Lessel, Davor
Kubisch, Christian
Precioso, Debora R.
Sillence, David
Hisama, Fuki M.
Dorschner, Michael
Martin, George M.
Oshima, Junko
CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title_full CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title_fullStr CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title_full_unstemmed CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title_short CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
title_sort ctc1 mutations in a brazilian family with progeroid features and recurrent bone fractures
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305643/
https://www.ncbi.nlm.nih.gov/pubmed/30393977
http://dx.doi.org/10.1002/mgg3.495
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