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

Autor: Sargolzaeiaval F; Department of Pathology, University of Washington, Seattle, Washington., Zhang J; Department of Pathology, University of Washington, Seattle, Washington., Schleit J; Department of Pathology, University of Washington, Seattle, Washington., Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Kubisch C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Precioso DR; Sarah Network of Rehabilitation Hospitals, Belo Horizonte, Brazil., Sillence D; Discipline of Genetic Medicine, Westmead Clinical School, Sydney Faculty of Medicine and Health, Westmead, Australia., Hisama FM; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington., Dorschner M; Department of Pathology, University of Washington, Seattle, Washington., Martin GM; Department of Pathology, University of Washington, Seattle, Washington., Oshima J; Department of Pathology, University of Washington, Seattle, Washington.; Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2018 Nov; Vol. 6 (6), pp. 1148-1156. Date of Electronic Publication: 2018 Nov 04.
DOI: 10.1002/mgg3.495
Abstrakt: 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.
(© 2018 University of Washington. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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