Figure 1

Mutations and protein structure of aggrecan. (a) Pedigrees of the six families with identified mutations in the ACAN gene. Both parents in families 2 und 3 presented with a height below/around −2 SDS. In both families the mother carrying the mutation was considered affected based on the phenotypic and radiographic evaluation (Table 1). (b) Model of the N-terminal Ig-___domain of ACAN highlighting the site of the p.(Cys51Gly) mutation. In the wildtype (top model), cysteine at position 51 (C51) forms a disulfide bond with cysteine at position 133 (C133) that stabilizes the ___domain (cysteines are shown in space-filled presentation; the sulfur atoms of both cysteines that form the disulfide bond are shown in yellow). In the mutant variant (bottom model) this disulfide bond cannot be formed, which is expected to reduce ___domain stability of even cause unfolding of the entire ___domain. (c) Model of the third Link ___domain of ACAN highlighting the site of the p.(Asp568Asn) mutation. In the wildtype (top model), aspartate at position 568 (D568) forms two polar interactions (dotted lines) with the histidine at position 481 (H481) and the tyrosine at position 489 (Y489). In the mutant variant (bottom model) only one of these interactions can be formed, which is expected to reduce ___domain stability. (d) Aggrecan is a proteoglycan consisting of different functional domains (modified from Gkourogianni et al., 2016). The G1 ___domain (blue) consists of an immunglobulin-like repeat (oval) and two proteoglycan tandem repeats (orbital)¹². The inter-globular ___domain separates it from the G2 ___domain (green) which consists of two proteoglycan tandem repeats (orbital). It is adjacent to the glycosaminoglycan attachment region (GAG) which carries keratan sulfate (dark blue) and chondroitin sulfate chains (orange). The C-terminal ___domain is the globular G3-___domain which consists of two EGF-repeats (violet), a C-type lectin ___domain (grey) and a complement regulatory protein repeat (turquoise). In the upper part the localization of the identified novel heterozygous mutations (P1-6) is shown (green: missense mutation, red: nonsense mutation). In the lower part, all previously reported mutations are shown (see Supplementary Table 1) (green: heterozygous missense mutation, red: heterozygous nonsense mutation, blue: homozygous missense mutation).