Fig. 4: Patient-derived cell lines and a mouse model of Catel–Manzke syndrome corroborate the molecular function of TGDS.
From: A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia
a, 3D reconstruction of the facial skeleton in individual 4. b–d, UDP-xylose (b), UDP-glucuronate (c) and UDP-6-deoxyhexose (d) were measured in fibroblasts from healthy controls and individuals with Catel–Manzke syndrome (ID1–5). Samples were analysed in two batches: individual 1 versus control 1; individuals 2–5 versus controls 2 and 3. e, Pathogenic variants of TGDS proteins. f, Western blot of Flag-tagged TGDS after transfection in U2OS cells. Quantification in Extended Data Fig. 6f and uncropped images in Supplementary Fig. 1. g,h, UDP-4-keto-6-deoxyglucose production by recombinant wild-type TGDS and indicated variants at 500 µM UDP-glucose for 24 h at 30 °C (g) or indicated UDP-glucose concentrations for 4 h at 30 °C (h). a.u., arbitrary units. i, Schematic of TgdsA100S/− (KI/KO) mice carrying p.Ala100Ser and a frameshift deletion–insertion, causing loss of function. Created in BioRender. Lyubenova, H. (2025) https://BioRender.com/hsez57t. j, µCT sagittal and coronary images of E18.5 wild-type and KI/KO embryos showing brachycephaly, with shorter mandibles and snouts. Measurements that are significantly different between wild-type and KI/KO embryos are indicated in yellow. k,l, Skeletal preparations showing shortened hindlimb (k) and forelimb (l) long bones in KI/KO E18.5 embryos. m–p, Quantification of UDP-4-keto-6-deoxyglucose (m), UDP-6-deoxyhexose (n), UDP-xylose (o) and UDP-glucuronate (p) in organ lysates from 8-month-old wild-type and KI/KO mice. ND, not detectable for technical reasons. Data are mean of two (h) or mean ± s.d. from four (b–d,g) independent experiments; from 11 wild-type (j–l) and 9 KI/KO (j–l) mice; or from 4 wild-type and KI/KO mice (m–p), normalized to wild-type or control conditions. *, # and † denote groups that are significantly different by two-tailed Sidak (b–d) or Dunnett (g) post hoc testing of log-transformed data after one-way ANOVA (b–d,g), Holm–Sidak corrected multiple t-tests (j–l) or multiple t-tests after log transformation (m–p). For exact P values see Source Data.
