Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta

Abstract

Osteogenesis imperfecta, discussed in Baldridge et al. 2008 is an inherited bone fragility disorder with a wide range of clinical severity that in the majority of cases is caused by mutations in COL1A1 or COL1A2, the genes that encode the two collagen type I alpha chains. Here we describe genotype-phenotype correlations in OI patients who have mutations affecting collagen type I. This paper is based on findings in a large single-centre OI population and a review of the literature.

Figure 1

Relationship between the positions of glycine substitutions in the triple helical domain of type I collagen and height z-scores in α1 chain of collagen I (a) and α2 chain of collagen I (b). The oblique solid line in B represents the regression line between the position of serine substitutions in α2 chain of collagen I and height (r = −0.73, P < 0.001; Spearman's rank correlation). The oblique dashed line in (b) represents the regression line between the position of aspartate substitutions in α2 chain of collagen I and height (r = −0.75, P < 0.001). A mutation closer to the carboxy-terminal end of the triple helical domain of alpha 2 chain had a more detrimental effect on height (b). No such correlation was observed in the alpha 1 chain (a), adapted with some modification from [11].

Figure 2

Relationship between the triple helical position of glycine mutations in collagen type I α chains and the presence (+) or absence (−) of dentinogenesis imperfecta (DI), adapted from [9].

Figure 3

Relationship between the triple helical position of glycine mutations in collagen type I α chains and the presence (+) or absence (−) of blue sclera, adapted from [9].

Figure 4

Iliac bone histomorphometric results in patients with COL1A1 haploinsufficiency mutations (HI), as well as with COL1A1 and COL1A2 mutations leading to glycine substitutions in the helical domain of collagen type I. Results are expressed as a percentage of the average result in the age-specific reference range [14]. The letters above the bars indicate the significance of the difference from 100% (i.e., the average result in healthy controls): a: P < 0.05; b: P < 0.01; c: P < 0.001. The significance of the variation between genotype groups is indicated by the symbols above the bar groups: ns = not significant; *P < 0.05; **P < 0.01; (a) C.Wi: core width; Ct.Wi: cortical width; BV/TV: bone volume per tissue volume; (b) O.Th: osteoid thickness; OS/BS: osteoid surface per bone surface, Ob.S/BS: osteoblast surface per bone surface; MAR: mineral apposition rate; MS/BS: mineralizing surface per bone surface; BFR/BS: bone-formation rate per bone surface, adapted with modification from [11].

Figure 5

Representative examples of iliac bone samples. (a) Haploinsufficiency mutation, in a 4-year-old boy with a c.1981C > T nucleotide change in COL1A1 that creates a stop codon (p.Gln661X). Core width 4.8 mm, cortical width 765 μm, bone volume per tissue volume 12.9%. (b) Helical glycine mutation, 9-year-old boy with a c.1090G > A nucleotide change in COL1A2 that creates an amino acid change (p.Gly364Ser). Core width 4.2 mm, cortical width 449 μm, and bone volume per tissue volume 8.9%, adapted from [11].

Figure 6

Basilar impression on brain MRI. The tip of the odontoid process (arrow) projects > 5 mm above the Chamberlain line (line between the hard palate and the opisthion which is the midpoint on the posterior margin of the foramen magnum).

Figure 7

Platybasia: a flat cranial base as a consequence of a flat nasion-sella-basion angle (Welcher basal angle or sphenoid angle > 140°).

Figure 8

Amino acid sequence of collagen α2 (I) between residues 1087 and 1111. Residues that are part of the triple-helical domain are shown on black background. The first residues of the C-telopeptide are shown in italics and on gray background. The asterisk indicates the glycine residue that is affected in a boy with OI type IV who has normal height and a normal appearance of hands and feet, adapted from [18].

Figure 9

Radiographs of hands and feet in a 15-year-old female. Small stubby hands and feet with hypoplastic nails (a, c). Severe shortening and thinning of all tubular bones including metacarpal and metatarsal bones, especially marked at the distal phalanges (b, d), adapted with modification from [18].