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Am J Hum Genet DOI:10.1016/j.ajhg.2014.04.003

Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy.

Publication TypeJournal Article
Year of Publication2014
AuthorsSergouniotis, PI, Chakarova, C, Murphy, C, Becker, M, Lenassi, E, Arno, G, Lek, M, MacArthur, DG, Bhattacharya, SS, Moore, AT, Holder, GE, Robson, AG, Wolfrum, U, Webster, AR, Plagnol, V
Corporate AuthorsUCL-Exomes Consortium
JournalAm J Hum Genet
Date Published2014 May 01
KeywordsAdult, Alleles, Animals, Carrier Proteins, Female, Genes, Recessive, Genetic Variation, Humans, Male, Mice, Middle Aged, Mutation, Pedigree, Peptide Synthases, Retinal Dystrophies

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID24791901
PubMed Central IDPMC4067560
Grant ListR01 GM104371 / GM / NIGMS NIH HHS / United States
1R01GM104371. / GM / NIGMS NIH HHS / United States
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom