Mutations in TUBB4B Cause a Distinctive Sensorineural Disease

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Mutations in TUBB4B Cause a Distinctive Sensorineural Disease Romain Luscan, Sabrina Mechaussier, Antoine Paul, Guoling Tian, Xavier Gérard, Sabine Defoort-Dellhemmes, Natalie Loundon, Isabelle Audo, Sophie Bonnin, Jean-François LeGargasson, Julien Dumont, Nicolas Goudin, Meriem Garfa-Traoré, Marc Bras, Aurore Pouliet, Bettina Bessières, Nathalie Boddaert, José-Alain Sahel, Stanislas Lyonnet, Josseline Kaplan, Nicholas J. Cowan, Jean-Michel Rozet, Sandrine Marlin, Isabelle Perrault The American Journal of Human Genetics Volume 101, Issue 6, Pages 1006-1012 (December 2017) DOI: 10.1016/j.ajhg.2017.10.010 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Heterozygous TUBB4B Substitutions Affecting Arg391 Cause LCA with Hearing Deficiency (A) Pedigrees of families and segregation analysis of the mutations. m1, c.1172G>A (p.Arg391His); m2, c.1171C>T (p.Arg391Cys); +, wild-type allele. P1, P2, and P3 are affected individuals whose fibroblasts were analyzed. The percentage below the genotype of individuals I2 in families 1 and 2 shows the relative abundance of mutant reads in genomic DNA from lymphocytes. (B) Sanger sequence traces around the mutation are shown below the corresponding pedigree. (C and D) Representative eye fundus views and audiograms in two individuals with TUBB4B substitutions affecting Arg391. The eldest individual’s funduscopy image displays features of advanced retinitis pigmentosa with a marked reduction in the caliber of retinal vessels, generalized choroid atrophy, marked macular rearrangements, and numerous pigmentary deposits in the periphery. The fundus of the youngest individual displays similar abnormalities, although to a much lesser extent (C). Left and right ear pure-tone audiograms of the two individuals displaying moderate symmetric hearing loss (left and central panels, respectively). Vocal audiograms (right panels) are consistent with pure-tone traces, suggesting that the two individuals have endocochlear deafness (D). The American Journal of Human Genetics 2017 101, 1006-1012DOI: (10.1016/j.ajhg.2017.10.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Functional Analysis of TUBB4B Mutations In Vitro, in Cultured Cells, and in Skin Fibroblasts (A and B) Folding in vitro. Plasmids encoding full-length TUBB4B (wild-type or containing the mutations shown) were expressed in rabbit reticulocyte lysate containing 35S-methionine. (A) Labeled reaction products analyzed by SDS-PAGE. Arrow: migration position of β-tubulin. (B) Kinetic analysis by native 4.5% PAGE of labeled reaction products done for the times shown (in min). In each panel, the right-hand track (marked with an asterisk) shows reactions chased with unlabeled native αβ-tubulin heterodimers, included so as to drive the heterodimer assembly reaction. Arrows (top to bottom): CCT/β-tubulin binary complex, TBCD/β-tubulin folding intermediate, prefoldin (PFD)/β-tubulin binary complex, αβ-tubulin heterodimer, and TBCA/β-tubulin folding intermediate. (C and D) Depressed MT growth rates in transfected COS7 cells (C) and in patient-derived skin fibroblasts (D) following recovery from cold-induced depolymerization. See Figures S2 and S3 for methods and statistical analyses. The American Journal of Human Genetics 2017 101, 1006-1012DOI: (10.1016/j.ajhg.2017.10.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions