Open AccessCTC 1 mutations in a Brazilian family with progeroid features and recurrent bone fractures
Author(s) -
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
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.495
Subject(s) - progeria , missense mutation , exome sequencing , genetics , werner syndrome , exome , telomere , biology , mutation , medicine , gene , rna , helicase
Background Cerebroretinal microangiopathy with calcifications and cysts ( CRMCC ) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 ( CTC 1 ) gene. The CTC 1 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 CTC 1 : 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 CTC 1 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 CTC 1 protein to GC ‐rich sequences. Conclusion CTC 1 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 .