A Recessive Skeletal Dysplasia, SEMD Aggrecan Type, Results from a Missense Mutation Affecting the C-Type Lectin Domain of Aggrecan Stuart W. Tompson,

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A Recessive Skeletal Dysplasia, SEMD Aggrecan Type, Results from a Missense Mutation Affecting the C-Type Lectin Domain of Aggrecan Stuart W. Tompson, Barry Merriman, Vincent A. Funari, Maryline Fresquet, Ralph S. Lachman, David L. Rimoin, Stanley F. Nelson, Michael D. Briggs, Daniel H. Cohn, Deborah Krakow The American Journal of Human Genetics Volume 84, Issue 1, Pages 72-79 (January 2009) DOI: 10.1016/j.ajhg.2008.12.001 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Phenotype (A) Pedigree. Filled symbols identify affected individuals. (B) In the top left image, the back row from left to right shows II-1 (23 years old [yo]) and I-I (58 yo), respectively, and the front row from left to right shows II-2 (19 yo), II-3 (16 yo), and II-4 (26 yo), respectively. Note the relative macrocephaly and lordosis in II-2 in the top right image, the telescoping fingers of II-3 in the lower left image, and the midface hypoplasia, relative prognathism, and low-set ears in II-4 in the lower right image. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Radiographic Phenotype (A), (B), and (D)–(F) are from II-4 at 9.5 yo, and (C) is from II-2 at 1 yo. Radiographs show (A) mild scoliosis, (B) platyspondyly, (C) clefts of the cervical-vertebral bodies (indicated by arrow), (D) shortening of the limbs with small irregular epiphyses and widened metaphyses, (E) an enlarged skull with midface hypoplasia, and (F) brachydactyly with extra carpal ossification centers. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Identity by Descent Mapping of the SEMD-Aggrecan-Type Locus Homozygosity maps for two of the affected siblings (II-4 and II-2) and one unaffected sibling (II-1) from the pedigree. Each plot shows the size of homozygous blocks for each chromosome across the genome, in centiMorgans, as inferred from SNP genotype data. The large blocks represent recent homozygosity by descent, suggesting ancestrally consanguineous parents. The only block that fits a consanguineous-recessive disease model is the chromosome 15 locus, which has the identical block of homozygosity in the affected siblings that is not shared identically with the unaffected sibling. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Prioritization of Genes within the Chromosome 15 Region with Respect to their Cartilage-Selective Gene Expression For each gene in the interval, cartilage gene expression was defined by the average expression in cartilage relative to the average expression in a panel of noncartilage tissues, indicated by pink squares with the scale on the left. The median derived coefficient of variation (CV; shown in blue), an indirect measure of expression in noncartilage tissues, was plotted for each gene with the scale indicated on the right. The genes in the interval were sorted by lowest CV (left) to highest CV (right). The threshold CV of 1 is marked by a horizontal red line. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 ACAN Mutation Analysis and Evolutionary Conservation of Aspartic-Acid Residue 2267 (A) Sequence traces derived from three family members, indicating the single-nucleotide change with the respective codon highlighted (red box). (B) Partial protein sequence of aggrecan showing the region containing Asp2267 among aggrecan orthologs as well as paralogous members of the lectican family of proteins. (C) Diagram of the aggrecan molecule showing N-terminal G1 and G2 globular domains, a highly repetitive central region modified with keratan sulfate (KS) and chondroitin sulfate (CS) side chains, and the C-terminal G3 globular domain where the mutation is located. In the expanded diagram of the G3 domain shown below, the red arrow indicates the location of the mutation in the C-type lectin (CLD) motif. Alternatively spliced epidermal growth factor-like (EGF) and complement regulatory protein-like (CRP) motifs are also shown. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 6 Biochemical Analyses of the Wild-Type and Mutant Aggrecan G3 Proteins (A) The effect of the D2267N mutation on the secretion of the aggrecan G3 domain. SDS-PAGE and western-blot analysis of conditioned media and cell lysates from 293-EBNA cells transiently transfected with the aggrecan G3 domain constructs (WT and mutant). Recombinant proteins were resolved on 4%–12% Bis-Tris gel under reducing conditions, transferred onto nitrocellulose membrane, and detected by western blotting with an antibody against an in-frame His tag. Recombinant WT G3 domains migrated at approximately 26 kDa for the short form and 40 kDa for the long form, whereas the mutant proteins migrated more slowly, with a mass of ∼45 kDa for both forms. Protein samples from cell lysates are shown in the left panel and from the culture media in the right panel for each form; the size of molecular weight (MW) markers is shown on the right. (B) N-glycanase digest of the mutated aggrecan G3 proteins. Western-blot analysis is of purified D2267N G3 protein with (digested) or without (undigested) N-glycanase treatment. The undigested D2267N protein appears as a diffuse ∼45 kDa band corresponding to the glycosylated form, which is in contrast to the digested form that becomes a sharp ∼26 kDa band for the short form and ∼40 kDa for the long form (similar to WT protein), indicating that the secreted mutated proteins possess N-glycan chains. (C) Binding analysis of recombinant aggrecan G3 domains to tenascin-C. The purity of the recombinant proteins was verified by silver staining of SDS-PAGE gel under reducing conditions (inset). The purified proteins were then tested for their ability to bind tenascin-C. Shown are representative sensograms (surface plasmon resonance, SPR) for WT G3 or D2267N G3 proteins at a concentration of 10 μg/ml. The proteins were injected at a flow rate of 30 μl/min for 3 min. The American Journal of Human Genetics 2009 84, 72-79DOI: (10.1016/j.ajhg.2008.12.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions