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Am J Hum Genet. 2014 May 1;94(5):760-9. doi: 10.1016/j.ajhg.2014.04.003.

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

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UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
UCL Institute of Ophthalmology, London EC1V 9EL, UK.
UCL Genetics Institute, London WC1E 6BT, UK.
Institute of Zoology, Focus Program Translational Neurosciences, Johannes Gutenberg University of Mainz, Mainz 55099, Germany.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK. Electronic address:


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.

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