Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts |
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| Authors: | Polvi Anne Linnankivi Tarja Kivelä Tero Herva Riitta Keating James P Mäkitie Outi Pareyson Davide Vainionpää Leena Lahtinen Jenni Hovatta Iiris Pihko Helena Lehesjoki Anna-Elina |
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| Institution: | 1. Folkhälsan Institute of Genetics, Helsinki 00290, Finland;2. Molecular Medicine Research Program, Research Programs Unit and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki 00290, Finland;3. Neuroscience Center, University of Helsinki, Helsinki 00290, Finland;4. Department of Pediatric Neurology, Children''s Castle, Helsinki University Central Hospital, Helsinki 00290, Finland;5. Department of Ophthalmology, Helsinki University Central Hospital, Helsinki 00290, Finland;6. Department of Pathology, Oulu University Hospital, Oulu 90029, Finland;7. Department of Pediatrics, Washington University School of Medicine, St. Louis Children''s Hospital, St. Louis, Missouri 63110, USA;8. Children''s Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland;9. Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico, C. Besta Neurological Institute, Milan 20133, Italy;10. Department of Pediatrics, Oulu University Hospital, Oulu 90029, Finland;11. Molecular Neurology Research Program, Research Programs Unit and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki 00290, Finland;12. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki 00271, Finland |
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| 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. |
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