Extended Data Fig. 6: Characterization of clinical manifestations and TGDS variants in individuals with Catel-Manzke syndrome.
From: A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia
a-c, Schematic representation of the TGDS variant in affected individual 3, abolishing the splice acceptor site of exon 6 (a; created in BioRender. Lyubenova, H. (2025) https://BioRender.com/l6uhom8), leading to a transcript lacking exon 6 as demonstrated by RT-PCR (b) and (c) sequencing, performed twice with the same result. d-e, Alphafold model of TGDS containing NAD+ and dTDP-glucose modeled based on the structure of prokaryotic dTDP-glucose dehydratases with Alphafill73 (d) or Alphafold model obtained with the Alphafold Multimer algorithm74 (e), predicting a dimeric protein. Amino acid variants observed in affected individuals are highlighted in green. V239, A100 and T102, as well as the region deleted in affected individual 3 are lining the catalytic pocket, whereas E90 and E322 are more peripheral. f, Quantification of TGDS expression normalized to GAPDH expression in U2OS cells transfected with the indicated variants containing a FLAG tag. Data are means ± SD from three independent experiments with two-tailed Dunnett post-hoc testing after one-way ANOVA. * denotes the only significant change (p-value 0.032). g, Photographs, radiographs and CT scans with 3D reconstruction of individuals (‘I’) with Catel-Manzke syndrome. Top row, hand radiographs of I2, I3 and I4. Lower row, hand photographs of I2 and I5 as well as cranial frontal CT scans with 3D reconstruction of I4. Right side, frontal and lateral whole body radiograph of I5 at 24 weeks of gestation, after pregnancy termination. Note radial deviation of the 2nd fingers in I2 and I5 as well as an accessory ossification center at the base of the 2nd proximal phalanx in I2 (Manzke dysostosis). Manzke dysostosis is a variable feature in Catel-Manzke syndrome. I3, I4 and I5 have clinodactyly of the 5th finger, I4 has additional clinodactyly of the 2nd, 3rd and 4th finger as well as distally enlarged metacarpals of the 2nd 3rd and 4th ray. Cranial CT scan of I4 shows asymmetric micrognathia. Whole body radiograph of I5 shows mildly shortened long bones, clinodactyly of the 5th fingers as well as micro- and retrognathia. I, individual; y, years; w, weeks; m, months.
