Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy

Publication type:
Journal article
Metadata:
Autoren
  • Panagiotis I Sergouniotis
  • Christina Chakarova
  • Cian Murphy
  • Mirjana Becker
  • Eva Lenassi
  • Gavin Arno
  • Monkol Lek
  • Daniel G MacArthur
  • Shomi S Bhattacharya
  • Anthony T Moore
  • Graham E Holder
  • Anthony G Robson
  • Uwe Wolfrum
  • Andrew R Webster
  • Vincent Plagnol
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000335485700010&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.ajhg.2014.04.003
eISSN
1537-6605
Externe Identifier
  • Clarivate Analytics Document Solution ID: AG5VB
  • PubMed Identifier: 24791901
ISSN
0002-9297
Ausgabe der Veröffentlichung
5
Zeitschrift
AMERICAN JOURNAL OF HUMAN GENETICS
Paginierung
760 - 769
Datum der Veröffentlichung
2014
Status
Published
Titel
Biallelic Variants in <i>TTLL5</i>, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy
Sub types
  • Article
Ausgabe der Zeitschrift
94

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Panagiotis I Sergouniotis
  • Christina Chakarova
  • Cian Murphy
  • Mirjana Becker
  • Eva Lenassi
  • Gavin Arno
  • Monkol Lek
  • Daniel G MacArthur
  • Shomi S Bhattacharya
  • Anthony T Moore
  • Graham E Holder
  • Anthony G Robson
  • Uwe Wolfrum
  • Andrew R Webster
  • Vincent Plagnol
DOI
10.1016/j.ajhg.2014.04.003
ISSN
0002-9297
Ausgabe der Veröffentlichung
5
Zeitschrift
The American Journal of Human Genetics
Sprache
en
Paginierung
760 - 769
Datum der Veröffentlichung
2014
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.ajhg.2014.04.003
Datum der Datenerfassung
2022
Titel
Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy
Ausgabe der Zeitschrift
94

Data source: Crossref

Abstract
In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(∗)45(;)Trp1118(∗)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(∗)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.
Addresses
  • UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
Autoren
  • Panagiotis I Sergouniotis
  • Christina Chakarova
  • Cian Murphy
  • Mirjana Becker
  • Eva Lenassi
  • Gavin Arno
  • Monkol Lek
  • Daniel G MacArthur
  • UCL-Exomes Consortium
  • Shomi S Bhattacharya
  • Anthony T Moore
  • Graham E Holder
  • Anthony G Robson
  • Uwe Wolfrum
  • Andrew R Webster
  • Vincent Plagnol
DOI
10.1016/j.ajhg.2014.04.003
eISSN
1537-6605
Externe Identifier
  • PubMed Identifier: 24791901
  • PubMed Central ID: PMC4067560
Funding acknowledgements
  • NIGMS NIH HHS: 1R01GM104371.
  • NIGMS NIH HHS: R01 GM104371
  • National Institute for Health Research (NIHR): ACF-2013-06-009
  • Wellcome Trust:
  • National Institute for Health Research (NIHR): NF-SI-0507-10204
  • Medical Research Council:
Open access
false
ISSN
0002-9297
Ausgabe der Veröffentlichung
5
Zeitschrift
American journal of human genetics
Schlüsselwörter
  • UCL-Exomes Consortium
  • Animals
  • Humans
  • Mice
  • Peptide Synthases
  • Carrier Proteins
  • Pedigree
  • Genes, Recessive
  • Mutation
  • Alleles
  • Adult
  • Middle Aged
  • Female
  • Male
  • Genetic Variation
  • Retinal Dystrophies
Sprache
eng
Medium
Print
Paginierung
760 - 769
Datum der Veröffentlichung
2014
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2014
Titel
Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy.
Sub types
  • brief-report
  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural
Ausgabe der Zeitschrift
94

Files

http://www.cell.com/article/S000292971400175X/pdf https://europepmc.org/articles/PMC4067560?pdf=render

Data source: Europe PubMed Central

Abstract
In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(∗)45(;)Trp1118(∗)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(∗)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.
Date of acceptance
2014
Autoren
  • Panagiotis I Sergouniotis
  • Christina Chakarova
  • Cian Murphy
  • Mirjana Becker
  • Eva Lenassi
  • Gavin Arno
  • Monkol Lek
  • Daniel G MacArthur
  • UCL-Exomes Consortium
  • Shomi S Bhattacharya
  • Anthony T Moore
  • Graham E Holder
  • Anthony G Robson
  • Uwe Wolfrum
  • Andrew R Webster
  • Vincent Plagnol
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/24791901
DOI
10.1016/j.ajhg.2014.04.003
eISSN
1537-6605
Externe Identifier
  • PubMed Central ID: PMC4067560
Funding acknowledgements
  • NIGMS NIH HHS: R01 GM104371
  • NIGMS NIH HHS: 1R01GM104371.
  • Wellcome Trust:
  • Medical Research Council:
Ausgabe der Veröffentlichung
5
Zeitschrift
Am J Hum Genet
Schlüsselwörter
  • Adult
  • Alleles
  • Animals
  • Carrier Proteins
  • Female
  • Genes, Recessive
  • Genetic Variation
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Pedigree
  • Peptide Synthases
  • Retinal Dystrophies
Sprache
eng
Country
United States
Paginierung
760 - 769
PII
S0002-9297(14)00175-X
Datum der Veröffentlichung
2014
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2014
Titel
Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy.
Sub types
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
94

Data source: PubMed

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