title: Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts.
abstract: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare multisystem disorder characterized by extensive intracranial calcifications and cysts, leukoencephalopathy, and retinal vascular abnormalities. Additional features include poor growth, skeletal and hematological abnormalities, and recurrent gastrointestinal bleedings. Autosomal-recessive inheritance has been postulated. The pathogenesis of CRMCC is unknown, but its phenotype has key similarities with Revesz syndrome, which is caused by mutations in TINF2, a gene encoding a member of the telomere protecting shelterin complex. After a whole-exome sequencing approach in four unrelated individuals with CRMCC, we observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. Sanger sequencing revealed seven more compound heterozygous mutations in eight more unrelated affected individuals. Two individuals who displayed late-onset cerebral findings, a normal fundus appearance, and no systemic findings did not have CTC1 mutations, implying that systemic findings are an important indication for CTC1 sequencing. Of the 11 mutations identified, four were missense, one was nonsense, two resulted in in-frame amino acid deletions, and four were short frameshift-creating deletions. All but two affected individuals were compound heterozygous for a missense mutation and a frameshift or nonsense mutation. No individuals with two frameshift or nonsense mutations were identified, which implies that severe disturbance of CTC1 function from both alleles might not be compatible with survival. Our preliminary functional experiments did not show evidence of severely affected telomere integrity in the affected individuals. Therefore, determining the underlying pathomechanisms associated with deficient CTC1 function will require further studies.
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Polvi
authors.forename: Tarja
authors.initials: T
authors.lastname: Linnankivi
authors.forename: Tero
authors.initials: T
authors.lastname: Kivelä
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: James P
authors.initials: JP
authors.lastname: Keating
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.forename: Leena
authors.initials: L
authors.lastname: Vainionpää
authors.forename: Jenni
authors.initials: J
authors.lastname: Lahtinen
authors.forename: Iiris
authors.initials: I
authors.lastname: Hovatta
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D002113:Calcification, Physiologic / Q000235:genetics*; D059345:Cerebral Small Vessel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003560:Cysts / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods; D016615:Telomere / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C544945:Ctc1 protein, human; D034501:Telomere-Binding Proteins