Funding/Support
The authors acknowledge support by grantsfrom the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR074813 and R01AR055655 and the National Institute on Aging (NIA) R01AG073349.
Author Contribution
Conceptualization: KS, MVR; Funding acquisition: MVR; Project administration: MVR; Visualization: KS; Writing - original draft: KS ;Writing - review & editing: KS, MVR.
Species | Gene | Disease model/disorder | Mutation | Effect | Phenotype | References |
---|---|---|---|---|---|---|
Chicken | Acan | Nanomelia | Nonsense mutation | Transversion c.4537G > T: convert glutamate at 1513 to a stop codon, creating defect in CS2 and G3 domain. Truncation of aggrecan; accumulation in ER | Embryonically lethal, short-limb dwarfism, large, brachycephalic head, abnormal mandible, and maxilla | Li et al., [28] 1993; Vertel et al., [29] 1993 |
Mouse | Acan | Cartilage matrix deficiency (cmd/cmd) | 7bp deletion in exon 5 | Deletion of B subdomain of N-terminal globular G1 domain, which binds to HA Aggrecan, results in truncation and secretion of mature aggrecan product in the matrix | Dwarfism, enlarged abdomen, short snout, cleft palate, and protruding tongue, respiratory failure related to pulmonary hypoplasia | Watanabe et al., [25] 1994 |
Mouse | Acan | Cartilage matrix deficiency (cmdbc) | Deletion of exons 2–18 | Deletion of the globular domains G1, G2, and GAG regions KS, CS1, and C2 domains. Consequent in aggrecan truncation | Dwarfism, enlarged abdomen, short snout, cleft palate, and protruding tongue | Krugger Jr et al., [24] 1999 |
Mouse | Bgn | Bgn-/0 | Deletion of exon 2 | Biglycan deficient | Thin dermis, low bone mass, larger irregular collagen fibril | Xu et al., [46] 1998; Chen et al., [45] 2002 |
Mouse | Bgn; Dcn | Bgn-/0 Dcn-/- | Double deletion using Bgn-/0 and Dcn-/- | Biglycan and decorin deficient | Compounding effect with loose disorganized dermis, larger highly irregular collagen fibrils in tendons | Robinson et al., [51] 2017 |
Mouse | Dcn | Dcn-/- | Deletion of exon 2 | Decorin deficient | Thin dermis, low bone mass, larger irregular collagen fibril | Danielson et al., [48] 1997 |
Mouse | Fmod | Fmod-/- | Deletion of exon 2 | Fibromodulin deficient | Abnormal tissue organization, thin collagen fibril diameter; abnormal dentin mineralization and alveolar bone formation | Gill et al., [56] 2002; Ameye et al., [59] 2002; Goldberg et al., [61] 2009 |
Mouse | Hspg2 | Hspg2-/- | Deletion of exon 6 | Mutant perlecan allele is transcribed, truncated protein could not be detected with a domain I–specific polyclonal antibody. Truncated form of domain I is not properly folded and is consequently degraded intracellularly as soon as it is translated | Homozygous mice died between E10–12 and perinatally. Embryos develop severe defect in cartilage, a tissue that lacks basement membranes. Reduced fibrillar collagen network shortened collagen fibers, and increased expression of cartilage ECM genes. Expansion of neuroepithelium, neuronal ectopias, and exencephaly | Costell et al., [87] 1999 |
Mouse | Hspg2 | Hspg2C1532Y−Neo | Substitution mutation | G-to-A substitution at Hspg2 nucleotide 4595, change amino acid from C to Y at residue 1532. Disrupt disulfide bond formation within perlecan domain III, thus affect perlecan conformation | Reduction of perlecan. Altered matrix organization and stiffness as function of age and genotype. Short stature, impaired mineralization, misshapen bones, osteoarthritis-like joint dysplasias and myotonia. Associated with SJS disease in humans | Rodgers et al., [89] 2007; Xu et al., [90] 2016; Ocken et al., [91] 2020 |
Mouse | Hspg2 | Hspg2Δ3/Δ3 | Deletion of exon 3 | Perlecan is devoid of ~20 kDa of domain I of its core protein and the GAG chains normally attached to this region; there was no detectable GAG substitution in domain V | GAGs accumulation in the nucleus pulposus, annulus fibrosus, and vertebral growth plates. Advanced chondrocyte hypertrophy and exostosis-like, ectopic bone formation at the cartilaginous endplate region | Shu et al., [92] 2019 |
Mouse | Prg4 | Prg4-/- | Deletion of exon 6 | Removal of mucin-like domain; lubricin deficient | Accelerated synovial hyperplasia, disappearance of superficial zone chondrocytes. Increase articular surface friction, increase apparent torsional modulus in L1/2 disc, thinner AF | Rhee et al., [41] 2005; Teeple et al., [111] 2015 |
Mouse | Sdc4 | Sdc4-/- | Deletion of exon 2-part of 4 | Deletion of ectodomain with three putative glycosaminoglycan attachment sites | Impaired wound healing and angiogenesis. Syndecan 4 regulates ADAMTS-5 and MMP3 under inflammatory milieu to degrade aggrecan. Essential for endochondral ossification to repair fracture healing. Exhibits smaller muscle fiber, defect in muscle regeneration after damage and myogenic satellite cell differentiation | Ishiguro et al., [74] 2000; Echtermeyer et al., [75] 2001; Cornelison et al., [77] 2004; Bertrand et al., [76] 2013; Rønning et al., [78] 2020; De Rossi et al., [76] 2021 |
Mouse | Tnmd | Tnmd-/- | Deletion of exon 1 | Tenomodulin deficient | Advanced degenerative of the disc, increase hypertrophic-like chondrocytes, apoptosis, small collagen fibrils with low compressive stiffness. Abnormal collagen I cross-linking, inferior endurance running performance | Lin et al., [110] 2020; Docheva et al., [63] 2005; Dex et al., [64] 2017 |
Mouse | Vcan | Prx1-Vcan | Deletion of exon 2 | Deletion of G1 domain; affect biosynthesis of versican | Distorted digits, tilted Joint surface and delayed cartilage development | Choocheep et al., [33] 2010; Higuchi et al., [34] 2021 |
Species | Gene | Disease model/disorder | Mutation | Effect | Phenotype | References |
---|---|---|---|---|---|---|
Human | ACAN | Spondyloepiphyseal dysplasia, Kimberley type (SEDK) | Frameshift mutation; autosomal dominant | A single-base-pair insertion, within the variable repeat region of exon 12, introduce a 212 amino acid frameshift followed by premature stop codon. Lack half of the CS1 domain, the complete CS2 domain, and the G3 domain, resulting in abnormally short aggrecan protein | Short stature and early development of osteoarthritis, especially in the knees, ankles, and hips. Variation of mutation also results in short stature with accelerated bone maturation, early onset of osteoarthritis, and craniofacial, limb, and vertebral abnormalities | Anderson et al., [114] 1990; Eyre et al., [115] 2005; Gleghorn et al., [116] 2005; Nilsson et al., [117] 2014; Kim et al., [118] 2022; Karatas et al., [119] 2023; Huang et al., [120] 2023 |
Human | ACAN | Spondyloepimetaphy-seal dysplasia (SEMD) | Missense mutation; autosomal dominant | Point mutation c.6799G > A p.Asp2267Asn amino acid substitution affected a highly conserved residue that contributes to the structure of the C-type lectin domain within the G3 domain of the protein, in part by coordinating binding of one of three calcium ions important for its structure | Heterogeneous group of disorders defined by the combination of vertebral, epiphyseal, and metaphyseal anomalies. Short stature, brachydactyly, distinct severe midface hypoplasia, short necks, barrel chests, lumbar lordosis, and macrocephaly | Tompson et al., [113] 2009; Fukuhara et al., [122] 2019; Stattin et al., [121] 2022 |
Human | BGN | X-linked SEMD | Spectrum of mutation: insertion/ deletion, missense, and nonsense | Mutation in BGN on chromosome Xq28. Point mutation c.439A > G (p.Lys147Glu) in Korean family; c.776G > T (p.Gly259Val) in the Italian family; and c.439A > G (p.Lys147Glu) mutation in the Indian patient | SEMDX were reported in three different ethnic background. Characterized by short stature with shortening of limbs, bowing of the legs, and lumbar lordosis | Camera et al., [123] 1994; Cho et al., [125] 2016; Meester et al., [124] 2017 |
Human | HSPG2 | Dyssegmental dysplasia, Silver-Handmaker type (DDSH) | Frameshift mutation; lethal autosomal recessive | 89-bp duplication of exon 34 of HSPG2; one unrelated case with 89-bp duplication compound with point mutation that results in skipping of entire exons 52 and 73. Homozygous 4-bp deletion in exon 31 causes frameshift mutation that results in truncation in the perlecan protein core | Diminished perlecan secretion. Dwarfism, anisospondyly and micromelia, small mouth, small chest, die shortly from respiratory insufficiency | Arikawa-Hirasawa et al., [126] 2001; Rieubland et al., [128] 2010; Ladhani et al., [129] 2013 |
Human | HSPG2 | Schwartz-Jampel syndrome (SJS) | Spectrum of mutations: insertion/ deletion, missense, and nonsense. Autosomal recessive | Spectrum of mutations affecting perlecan domain II, III, IV, V. For example: Point mutation c.2746C>T on exon 22 from one parent results in premature stop codon (p.R916X), reducing perlecan mRNA level by 36.3%. Another case found c.1125C > G; p.Cys375Trp of HSPG2 affect perlecan domain II | Continuous contractions of muscles throughout the body including the face, abnormal spinal curvature and shortening of the bone. Narrow eye openings (blepharophimosis) and pursed lips | Bauché et al., [130] 2013; Lin et al., [131] 2021 |