FIGURE 1 a) Three-generation pedigree of the proband. Numbers below individual symbols are age at death or study. NOP10 mutation status in subjects for whom DNA was available for sequencing and pulmonary and extra-pulmonary phenotype is also depicted. (+/c.17A>G) discloses obligate carrier state. In the insert, the presence of NOP10 mutation identified by whole exome sequencing was confirmed by Sanger sequencing. The symbol +/+ discloses wild type and +/c.17A>G heterozygosity for the mutation. TL: telomere length by flowFISH. b) High-resolution computed tomography (HRCT) image at the basal segments of the lower lobes of the proband (II.1) showing peripheral fine reticulation with a microcystic pattern subpleurally. In the inner lung zones intralobular reticulation in association with thin wall traction bronchiectasis are depicted. All features indicate the fibrotic nature of the process. c) HRCT of the chest at the level of the basal segments of lower lobes of the patient II.7 revealing definite reticulation subpleurally with areas of increased density resulting from coalescence of the reticular opacities and areas of microatelectasis. Reticular changes are also seen more centrally distorting the shape of the vessels, while few areas of macrocystic (honeycomb) changes are seen in contact with the mediastinal pleura. The lungs bilaterally are ill expanded (small volumes). d) Ribbon representation of the model of human NOP10, within the frame of a whole H/ACA RNP complex (experimental three-dimensional structure from Pyroccoccus furiosus, PDB 2EY4). A model of the three-dimensional structure of human NOP10 has been made considering, for its N-terminal region (aa 1–33), the experimental three-dimensional structure of Saccharomyces cerevisiae Nop10 (solved in complex with Cbf5/Dkc1 and Gar1 (pdb 3U28 [11]) and, for the C-terminal region (aa 34–65), the experimental 3D structure of Pyrococcus furiosus Nop10, folded in part into an alpha-helix when contacting both Cbf5 and L7ae/Nhp2 (pdb 2EY4 [12]). The three-dimensional structure of human NOP10 could not be modelled as a whole starting from the archaeal Nop10 three-dimensional structure, as the N-terminal sequences strikingly diverge between archaeal and eukaryotic species, although still sharing a similar “ribbon” fold, organised like a beta barrel [11]. The model of the human NOP10 3D structure was then superimposed with the frame of the whole H/ACA RNP structure, as observed for archaeal complexes (PDB 2EY4). This superimposition is supported by the fact that the structure of the individual subunits, overall organisation and interfaces are similar between archaeal and yeast H/ACA RNP complexes [11]. Tyr6 is buried with the small, N-terminal globular, ribbon domain of NOP10 and likely plays a critical for the stability of this domain, in close contact with human Dyskerin DKC1 (Cbf5). In archaeal proteins, the corresponding position is occupied by one of the four cysteine encapsulating a zinc ion within the ribbon domain [11]. The name of the human subunits of the H/ACA RNP complex are given within brackets. Molecular graphics and analyses were performed using the UCSF Chimera package [13]. Models of the three-dimensional structure were built using Modeller 9v15 [14], according to the alignment presented in Li et al. [11].