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Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants

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Abstract

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient’s condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r =  − 0.603, p = 0.01) and the clinical manifestation score (r =  − 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce “spondyloepiphyseal dysplasia, COMP type”. Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.

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Data Availability

The raw datasets generated and/or analyzed during this study are not publicly available but are available from the corresponding author upon reasonable request.

Change history

  • 04 March 2023

    Missing ESM files has been added in the article.

Abbreviations

PSACH:

Pseudoachondroplasia

MED1:

Multiple epiphyseal dysplasia type 1

COMP:

Cartilage oligomeric matrix protein

NTD:

N-terminal domain

T2:

Epidermal-growth factor-like domains

T3:

Calmodulin-like domains

CTD:

C-terminal domain

BMI:

Body mass index

KDOQI:

Kidney Disease Outcomes Quality Initiative

PCR:

Polymerase chain reaction

M ± SD:

Mean ± standard deviation

IQR:

Interquartile range

y.o.:

Years old

GH:

Growth hormone

IGF-1:

Insulin-like growth factor 1

Ca:

Calcium

P:

Phosphorus

ALP:

Alkaline phosphatase

β-CTX:

C-terminal cross-linking telopeptide of type I collagen

25OHD:

25-Hydroxyvitamin D

rhGH:

Recombinant human growth hormone

ER:

Endoplasmic reticulum

References

  1. Briggs MD, Brock J, Ramsden SC, Bell PA (2014) Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias. Eur J Hum Genet 22:1278–1282. https://doi.org/10.1038/ejhg.2014.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES et al (1995) Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 10:330–336. https://doi.org/10.1038/ng0795-330

    Article  CAS  PubMed  Google Scholar 

  3. Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M et al (1995) Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 10:325–329. https://doi.org/10.1038/ng0795-325

    Article  CAS  PubMed  Google Scholar 

  4. Briggs MD, Wright MJ (1993) Pseudoachondroplasia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, Seattle (Updated 16 Aug 2018)

    Google Scholar 

  5. Unger S, Bonafe L, Superti-Furga A (2008) Multiple epiphyseal dysplasia: clinical and radiographic features, differential diagnosis and molecular basis. Best Pract Res Clin Rheumatol 22:19–32. https://doi.org/10.1016/j.berh.2007.11.009

    Article  CAS  PubMed  Google Scholar 

  6. Briggs MD, Wright MJ, Mortier GR (1993) Multiple epiphyseal dysplasia, autosomal dominant. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, Seattle (Updated 25 April 2019)

    Google Scholar 

  7. Posey KL, Hayes E, Haynes R, Hecht JT (2004) Role of TSP-5/COMP in pseudoachondroplasia. Int J Biochem Cell Biol 36:1005–1012. https://doi.org/10.1016/j.biocel.2004.01.011

    Article  CAS  PubMed  Google Scholar 

  8. Acharya C, Yik JH, Kishore A, Van Dinh V, Di Cesare PE, Haudenschild DR (2014) Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: interaction, regulation and role in chondrogenesis. Matrix Biol J Int Soc Matrix Biol 37:102–111. https://doi.org/10.1016/j.matbio.2014.06.001

    Article  CAS  Google Scholar 

  9. Tan K, Duquette M, Joachimiak A, Lawler J (2009) The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding. FASEB J Off Publ Fed Am Soc Exp Biol 23:2490–2501. https://doi.org/10.1096/fj.08-128090

    Article  CAS  Google Scholar 

  10. Newton G, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Lawler J (1994) Characterization of human and mouse cartilage oligomeric matrix protein. Genomics 24:435–439. https://doi.org/10.1006/geno.1994.1649

    Article  CAS  PubMed  Google Scholar 

  11. Kleerekoper Q, Hecht JT, Putkey JA (2002) Disease-causing mutations in cartilage oligomeric matrix protein cause an unstructured Ca2+ binding domain. J Biol Chem 277:10581–10589. https://doi.org/10.1074/jbc.M109944200

    Article  CAS  PubMed  Google Scholar 

  12. Unger S, Hecht JT (2001) Pseudoachondroplasia and multiple epiphyseal dysplasia: new etiologic developments. Am J Med Genet 106:244–250

    Article  CAS  PubMed  Google Scholar 

  13. Di Cesare PE, Fang C, Leslie MP, Tulli H, Perris R, Carlson CS (2000) Expression of cartilage oligomeric matrix protein (COMP) by embryonic and adult osteoblasts. J Orthop Res Off Publ Orthop Res Soc 18:713–720. https://doi.org/10.1002/jor.1100180506

    Article  Google Scholar 

  14. Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J (2005) Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J Biol Chem 280:32655–32661. https://doi.org/10.1074/jbc.M504778200

    Article  CAS  PubMed  Google Scholar 

  15. Chen FH, Herndon ME, Patel N, Hecht JT, Tuan RS, Lawler J (2007) Interaction of cartilage oligomeric matrix protein/thrombospondin 5 with aggrecan. J Biol Chem 282:24591–24598. https://doi.org/10.1074/jbc.M611390200

    Article  CAS  PubMed  Google Scholar 

  16. Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P (2001) Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. J Biol Chem 276:6083–6092. https://doi.org/10.1074/jbc.M009512200

    Article  CAS  PubMed  Google Scholar 

  17. Li H, Ji C, Zong X, Zhang Y (2009) Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Chin J Pediatr 47:487–492

    Google Scholar 

  18. Li H, Ji C, Zong X, Zhang Y (2009) Body mass index growth carves for Chinese children and adolescents aged 0 to 18 years. Chin J Pediatr 47:493–498

    Google Scholar 

  19. KW Group (2009) KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update. Executive summary. Am J Kidney Dis Off J Natl Kidney Found 53:S11-104. https://doi.org/10.1053/j.ajkd.2008.11.017

    Article  Google Scholar 

  20. Rauchenzauner M, Schmid A, Heinz-Erian P, Kapelari K, Falkensammer G, Griesmacher A, Finkenstedt G, Högler W (2007) Sex- and age-specific reference curves for serum markers of bone turnover in healthy children from 2 months to 18 years. J Clin Endocrinol Metab 92:443–449. https://doi.org/10.1210/jc.2006-1706

    Article  CAS  PubMed  Google Scholar 

  21. Briggs MD, Chapman KL (2002) Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat 19:465–478. https://doi.org/10.1002/humu.10066

    Article  CAS  PubMed  Google Scholar 

  22. Yu WJ, Zhang Z, He JW, Fu WZ, Wang C, Zhang ZL (2016) Identification of two novel mutations in the COMP gene in six families with pseudoachondroplasia. Mol Med Rep 14:2180–2186. https://doi.org/10.3892/mmr.2016.5486

    Article  CAS  PubMed  Google Scholar 

  23. Posey KL, Veerisetty AC, Liu P, Wang HR, Poindexter BJ, Bick R, Alcorn JL, Hecht JT (2009) An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype. Am J Pathol 175:1555–1563. https://doi.org/10.2353/ajpath.2009.090184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Posey KL, Hecht JT (2017) Novel therapeutic interventions for pseudoachondroplasia. Bone 102:60–68. https://doi.org/10.1016/j.bone.2017.03.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Svensson L, Aszodi A, Heinegard D, Hunziker EB, Reinholt FP, Fassler R, Oldberg A (2002) Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol 22:4366–4371. https://doi.org/10.1128/MCB.22.12.4366-4371.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD (2007) Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet 16:2072–2088. https://doi.org/10.1093/hmg/ddm155

    Article  CAS  PubMed  Google Scholar 

  27. Posey KL, Coustry F, Hecht JT (2018) Cartilage oligomeric matrix protein: COMPopathies and beyond. Matrix Biol J Int Soc Matrix Biol 71–72:161–173. https://doi.org/10.1016/j.matbio.2018.02.023

    Article  CAS  Google Scholar 

  28. Posey KL, Coustry F, Veerisetty AC, Liu P, Alcorn JL, Hecht JT (2012) Chop (Ddit3) is essential for D469del-COMP retention and cell death in chondrocytes in an inducible transgenic mouse model of pseudoachondroplasia. Am J Pathol 180:727–737. https://doi.org/10.1016/j.ajpath.2011.10.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pirog KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD (2014) Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia. PLoS ONE 9:e85145. https://doi.org/10.1371/journal.pone.0085145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD (2012) Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat 33:144–157. https://doi.org/10.1002/humu.21611

    Article  CAS  PubMed  Google Scholar 

  31. Sakamoto Y, Yamamoto T, Kajino Y, Kabata T, Tsuchiya H, Miyake N, Iwamoto Y, Matsumoto N, Ikegawa S (2017) Multiple epiphyseal dysplasia mimicking osteoarthritis due to acetabular dysplasia: a report of a familial case with a COMP mutation. J Orthop Sci Off J Jpn Orthop Assoc 22:967–971. https://doi.org/10.1016/j.jos.2016.01.010

    Article  Google Scholar 

  32. Shao J, Zhao S, Yan Z, Wang L, Zhang Y, Lin M, Yu C, Wang S, Niu Y, Li X, Qiu G, Zhang J, Wu Z, Wu N (2020) A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia. BMC Med Genet 21:115. https://doi.org/10.1186/s12881-020-01040-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mabuchi A, Momohara S, Ohashi H, Takatori Y, Haga N, Nishimura G, Ikegawa S (2004) Circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations. Am J Med Genet A 129:35–38. https://doi.org/10.1002/ajmg.a.30164

    Article  Google Scholar 

  34. Guo BB, Jin JY, Yuan ZZ, Zeng L, Xiang R (2021) A novel COMP mutated allele identified in a Chinese family with pseudoachondroplasia. BioMed Res Int 2021:6678531. https://doi.org/10.1155/2021/6678531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Coustry F, Posey KL, Maerz T, Baker K, Abraham AM, Ambrose CG, Nobakhti S, Shefelbine SJ, Bi X, Newton M, Gawronski K, Remer L, Veerisetty AC, Hossain MG, Chiu F, Hecht JT (2018) Mutant cartilage oligomeric matrix cartilage (COMP) compromises bone integrity, joint function and the balance between adipogenesis and osteogenesis. Matrix Biol J Int Soc Matrix Biol. https://doi.org/10.1016/j.matbio.2017.12.014

    Article  Google Scholar 

  36. Tufan AC, Satiroglu-Tufan NL, Jackson GC, Semerci CN, Solak S, Yagci B (2007) Serum or plasma cartilage oligomeric matrix protein concentration as a diagnostic marker in pseudoachondroplasia: differential diagnosis of a family. Eur J Hum Genet 15:1023–1028. https://doi.org/10.1038/sj.ejhg.5201882

    Article  CAS  PubMed  Google Scholar 

  37. Liu FX, Li ZL, Wei ZJ, Meng Y, Ren CA, Zhang XD, Yu MX, Huang SZ (2010) Genetic analysis and serum level of cartilage oligomeric matrix protein in patients with pseudoachondroplasia. Chin Med J 123:2181–2184

    CAS  PubMed  Google Scholar 

  38. Weiner DS, Guirguis J, Makowski M, Testa S, Shauver L, Morgan D (2019) Orthopaedic manifestations of pseudoachondroplasia. J Child Orthop 13:409–416. https://doi.org/10.1302/1863-2548.13.190066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mabuchi A, Manabe N, Haga N, Kitoh H, Ikeda T, Kawaji H, Tamai K, Hamada J, Nakamura S, Brunetti-Pierri N, Kimizuka M, Takatori Y, Nakamura K, Nishimura G, Ohashi H, Ikegawa S (2003) Novel types of COMP mutations and genotype–phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet 112:84–90. https://doi.org/10.1007/s00439-002-0845-9

    Article  CAS  PubMed  Google Scholar 

  40. Kennedy J, Jackson G, Ramsden S, Taylor J, Newman W, Wright MJ, Donnai D, Elles R, Briggs MD (2005) COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. Eur J Hum Genet 13:547–555. https://doi.org/10.1038/sj.ejhg.5201374

    Article  CAS  PubMed  Google Scholar 

  41. Anthony S, Munk R, Skakun W, Masini M (2015) Multiple epiphyseal dysplasia. J Am Acad Orthop Surg 23:164–172. https://doi.org/10.5435/JAAOS-D-13-00173

    Article  PubMed  Google Scholar 

  42. Balasubramanian K, Li B, Krakow D, Nevarez L, Ho PJ, Ainsworth JA, Nickerson DA, Bamshad MJ, Immken L, Lachman RS, Cohn DH (2017) MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1. Am J Med Genet A 173:2415–2421. https://doi.org/10.1002/ajmg.a.38349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y (2003) Efficacy of growth hormone therapy for patients with skeletal dysplasia. J Bone Miner Metab 21:307–310. https://doi.org/10.1007/s00774-003-0425-7

    Article  CAS  PubMed  Google Scholar 

  44. Posey KL, Coustry F, Veerisetty AC, Hossain M, Alcorn JL, Hecht JT (2015) Antioxidant and anti-inflammatory agents mitigate pathology in a mouse model of pseudoachondroplasia. Hum Mol Genet 24:3918–3928. https://doi.org/10.1093/hmg/ddv122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Our deepest thanks to all of the participants in this study and Dr. Yuelun Zhang for whose kind help in statistics. This study was supported by the National Natural Science Foundation of China (Nos. 81900811, 81170805, and 81670714), and the Chinese Academy of Medical Sciences-CAMS Innovation Fund for Medical Sciences (CAMS-2016–12 M-3-003).

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Authors and Affiliations

  1. Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China

    Hanting Liang, Yanfang Hou, Qianqian Pang, Yan Jiang, Ou Wang, Mei Li, Xiaoping Xing, Huijuan Zhu & Weibo Xia

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  1. Hanting Liang
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Contributions

WBX designed the study and revised the manuscript. HTL and YFH analyzed the genetic results. HTL draft the manuscript. QQP sampled the serum. YJ, OW, ML, XPX and HJZ collected the clinical information of the patients. HTL and WBX are responsible for the integrity of the data analysis. All authors read and approved the final manuscript.

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Correspondence to Weibo Xia.

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The study was performed with the approval of the Ethics Committee of Peking Union Medical College Hospital (JS-1689).

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Liang, H., Hou, Y., Pang, Q. et al. Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants. Calcif Tissue Int 110, 313–323 (2022). https://doi.org/10.1007/s00223-021-00920-6

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