Panel A shows the pedigree of the affected family; the patients’ grandmothers were sisters. (The arrow indicates the proband.) In Panel B, top row, radiographs of Patient III-4 show the long bones of the lower limbs at 1 month of age (the two films on the left) and the thorax and lateral spine at 1.25 years of age (the two films on the right). Her long bones are poorly modeled, with severe bowing, osteopenia, and thin cortices, and her thorax is long and narrow, with anterior compressions of T11 through L2. Panel B, bottom row, shows radiographs of the skull, thorax, and legs of Patient III-1. His skull shows frontal bossing but no wormian bones, his thorax is long and narrow, and the long bones of his lower limbs are osteopenic, with thin cortices and mild metaphyseal flaring but with generally good modeling. Panel C shows the homozygous change in the peptidyl-prolyl isomerase B (PPIB) start codon from methionine to arginine in the proband (Patient III-4). This substitution was confirmed by NlaIII restriction-enzyme digestion of genomic DNA, as shown in Panel D, with homozygosity in both patients and heterozygosity in their parents and unaffected siblings. The asterisk indicates the mutant band.

Western blots of fibroblast CyPB, CRTAP, and P3H1 in the proband (III-4) and her father (II-3), compared with actin antibody–loading controls, are shown in Panel A. The lack of CyPB protein and decreases in CRTAP and P3H1 in the proband corroborate the results of immunofluorescence staining. Immunofluorescence staining of fibroblasts from the proband and from a control subject, colocalized with endoplasmic reticulum marker PDI or GRP94, are shown for the three components of the prolyl 3-hydroxylation complex — cyclophilin B (CyPB) in Panel B, cartilage-associated protein (CRTAP) in Panel C, and prolyl 3-hydroxylase 1 (P3H1) in Panel D. The cells from the proband show no signal for CyPB, with a decrease in staining of both CRTAP and P3H1. Panel E shows the steady-state type I collagen protein in fibroblasts from the proband and from a control subject. Migration of the alpha chains (α1[V], α1[I], and α2[I]) in the cell layer is normal in the proband, and the α1(I) collagen band is minimally broadened.