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

Research output: Contribution to journalArticle

91 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)540-549
Number of pages10
JournalAmerican Journal of Human Genetics
Volume90
Issue number3
DOIs
Publication statusPublished - Mar 9 2012

Fingerprint

Telomere
Maintenance
Mutation
Frameshift Mutation
Nonsense Codon
Exome
Leukoencephalopathies
Retinal Vessels
Missense Mutation
Cysts
Alleles
Cerebroretinal Microangiopathy with Calcifications and Cysts
Hemorrhage
Phenotype
Amino Acids
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. / 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.

In: American Journal of Human Genetics, Vol. 90, No. 3, 09.03.2012, p. 540-549.

Research output: Contribution to journalArticle

Polvi, A, Linnankivi, T, Kivelä, T, Herva, R, Keating, JP, Mäkitie, O, Pareyson, D, Vainionpää, L, Lahtinen, J, Hovatta, I, Pihko, H & Lehesjoki, AE 2012, 'Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts', American Journal of Human Genetics, vol. 90, no. 3, pp. 540-549. https://doi.org/10.1016/j.ajhg.2012.02.002
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. / Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 3. pp. 540-549.
@article{2739b0b0581948938d6d3d80d89b4342,
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.",
author = "Anne Polvi and Tarja Linnankivi and Tero Kivel{\"a} and Riitta Herva and Keating, {James P.} and Outi M{\"a}kitie and Davide Pareyson and Leena Vainionp{\"a}{\"a} and Jenni Lahtinen and Iiris Hovatta and Helena Pihko and Lehesjoki, {Anna Elina}",
year = "2012",
month = "3",
day = "9",
doi = "10.1016/j.ajhg.2012.02.002",
language = "English",
volume = "90",
pages = "540--549",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts

AU - Polvi, Anne

AU - Linnankivi, Tarja

AU - Kivelä, Tero

AU - Herva, Riitta

AU - Keating, James P.

AU - Mäkitie, Outi

AU - Pareyson, Davide

AU - Vainionpää, Leena

AU - Lahtinen, Jenni

AU - Hovatta, Iiris

AU - Pihko, Helena

AU - Lehesjoki, Anna Elina

PY - 2012/3/9

Y1 - 2012/3/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84858076515&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858076515&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2012.02.002

DO - 10.1016/j.ajhg.2012.02.002

M3 - Article

C2 - 22387016

AN - SCOPUS:84858076515

VL - 90

SP - 540

EP - 549

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -