Mutations in CTC1, Encoding the CTS Telomere Maintenance Complex Component 1, Cause Cerebroretinal Microangiopathy with Calcifications and Cysts Anne.

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Mutations in CTC1, Encoding the CTS Telomere Maintenance Complex Component 1, Cause Cerebroretinal Microangiopathy with Calcifications and Cysts Anne Polvi,

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Mutations in CTC1, Encoding the CTS Telomere Maintenance Complex Component 1, Cause Cerebroretinal Microangiopathy with Calcifications and Cysts Anne Polvi, Tarja Linnankivi, Tero Kivelä, Riitta Herva, James P. Keating, Outi Mäkitie, Davide Pareyson, Leena Vainionpää, Jenni Lahtinen, Iiris Hovatta, Helena Pihko, Anna-Elina Lehesjoki The American Journal of Human Genetics Volume 90, Issue 3, Pages 540-549 (March 2012) DOI: 10.1016/j.ajhg.2012.02.002 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Key Clinical Findings in CRMCC (A) A T2-weighted magnetic resonance image (MRI) of a CRMCC-affected individual (age 11 years) shows heterogeneous lesions in both thalami (black arrows), hyperintensity in the posterior parts of the internal capsules (white arrow) and in the right putamen, and a cyst in the midline (arrowhead). (B) A T2∗-weighted image reveals large calcifications in thalami (arrow) and in the parieto-occipital regions. (C) A T2-weighted image of another individual (age 16 years) with CRMCC shows hyperintense lesions in the brain stem (arrow). (D and E) Flair images of a 3-year-old individual reveal widespread white-matter hyperintensity in the parieto-occipital regions (arrowheads) as well as asymmetric thalamic involvement (black arrow). A stripe-like hypodensity in the subcortical white matter is seen (white arrow) and most likely represents calcification. Note a midline cyst. (F) A brain computed tomography (CT) image of a 3-year-old individual shows dense calcifications in the subcortical white matter (arrowheads) and in the brainstem (arrow). (G and H) Wide-angle fundus photographs of a 15-month-old individual's eyes show a preretinal hemorrhage (arrow) associated with telangiectatic retinal vessels (arrowheads), which border avascular peripheral retina in the right eye (G), and an exudative retinal detachment with yellow lipid exudates in the left eye (H). (I) Radiographs of the lower limbs of a 14-year-old individual show osteopenia and abnormal bone structure (especially in the metaphyseal areas), bilateral fragility fractures in the proximal tibiae (arrows), and genua valga. The American Journal of Human Genetics 2012 90, 540-549DOI: (10.1016/j.ajhg.2012.02.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic Structure of CTC1 and the Encoded Protein with Relative Positions of the Mutations The exons in CTC1 are shown to scale as numbered boxes. The untranslated regions are depicted in gray. The introns are shown as lines and are not to scale. In CTC1, the predicted OB folds are shown as gray boxes. The N-terminal 700 aa region was previously shown to be involved in DNA binding, which is possibly mediated by the two OB domains, and the following C-terminal region in STN1 binding.14 The American Journal of Human Genetics 2012 90, 540-549DOI: (10.1016/j.ajhg.2012.02.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Twelve Pedigrees with CRMCC-Associated CTC1 Mutations Symbols filled with black indicate individuals for whom clinical data were available for the diagnosis of CRMCC. The affection status of individuals F6:II-1 and F9:II-1 (symbols filled with gray) is unknown; their intrauterine growth was severely retarded, they were born prematurely at gestational weeks 36 and 31+3, respectively, and they died soon after birth but were not investigated further. Individual F6:II-2 had clinically definite CRMCC, but his detailed clinical data and DNA were not available for this study. The identified mutations at the protein level are shown below each genotyped individual. DNA samples were available for all individuals with CTC1 alleles indicated, except for F4:II-2 and F7:II-3, from whom only clinical information was available and for whom the genotypes (in parentheses) were inferred from parental genotypes. “wt” denotes no mutation. The American Journal of Human Genetics 2012 90, 540-549DOI: (10.1016/j.ajhg.2012.02.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Conservation of the CTC1 Amino Acid Sequence among Different Species Amino acid sequence alignments around the single amino acids affected by five CRMCC mutations are shown for selected species. The figure is modified from data displayed in Ensembl Comparative Genomics Gene Tree alignment for CTC1. The amino acids affected by a missense mutation or a 1 aa deletion in the individuals with CRMCC are highlighted with black. Mutation descriptions are indicated under the sequences. PolyPhen16 analysis predicted the p.Ala227Val mutation to be possibly damaging and predicted the three other missense mutations to be probably damaging. The American Journal of Human Genetics 2012 90, 540-549DOI: (10.1016/j.ajhg.2012.02.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 Telomere Length in CRMCC-Affected, Heterozygous Carrier, and Control Individuals Relative telomere length was determined for seven CRMCC-affected individuals (ages 1–16 years) and their 41 controls (ages 7–21years; age matched +/− 5 years) as well as for nine heterozygous-mutation carriers (unaffected parents, ages 30–47 years) and their 29 controls (ages 30–52 years; age matched +/− 5 years). For telomere-length measurement, leukocyte DNA of selected individuals, matched for the DNA-extraction method, was studied by a quantitative PCR-based method,29 as described before,30,31 with small modifications. PCR reactions were run with a Biorad CFX384 PCR machine controlled by the CFX Manager 2.0 software. All samples were analyzed in triplicate. Quality control was performed as described previously.31 Data analysis was carried out in Microsoft Office Excel 2007. Samples were removed from the data analysis if their values deviated more than 3 standard deviations from the mean (N = 2). No significant differences were observed between affected or carrier and control individuals (Student's t test). The error bars represent standard deviation. The American Journal of Human Genetics 2012 90, 540-549DOI: (10.1016/j.ajhg.2012.02.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions