1932

Abstract

Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.

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2015-08-24
2024-03-29
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Literature Cited

  1. Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver EJ. 1.  et al. 1991. Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy).. PNAS 88:6624–27 [Google Scholar]
  2. Akizu N, Silhavy JL, Rosti RO, Scott E, Fenstermaker AG. 2.  et al. 2014. Mutations in CSPP1 lead to classical Joubert syndrome. Am. J. Hum. Genet. 94:80–86 [Google Scholar]
  3. Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS. 3.  2010. Novel CENPJ mutation causes Seckel syndrome. J. Med. Genet. 47:411–14 [Google Scholar]
  4. Allen DB, Cuttler L. 4.  2013. Short stature in childhood—challenges and choices. N. Engl. J. Med. 368:1220–28 [Google Scholar]
  5. Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A. 5.  et al. 2012. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat. Genet. 44:788–92 [Google Scholar]
  6. Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y. 6.  1999. Perlecan is essential for cartilage and cephalic development. Nat. Genet. 23:354–58 [Google Scholar]
  7. Arikawa-Hirasawa E, Wilcox WR, Le AH, Silverman N, Govindraj P. 7.  et al. 2001. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat. Genet. 27:431–34 [Google Scholar]
  8. Asharani PV, Keupp K, Semler O, Wang W, Li Y. 8.  et al. 2012. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am. J. Hum. Genet. 90:661–74 [Google Scholar]
  9. Baker S, Booth C, Fillman C, Shapiro M, Blair MP. 9.  et al. 2011. A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. Am. J. Med. Genet. A 155A:1668–72 [Google Scholar]
  10. Baldridge D, Shchelochkov O, Kelley B, Lee B. 10.  2010. Signaling pathways in human skeletal dysplasias. Annu. Rev. Genomics Hum. Genet. 11:189–217 [Google Scholar]
  11. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ. 11.  et al. 2011. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12:745–55 [Google Scholar]
  12. Bannister AJ, Kouzarides T. 12.  2011. Regulation of chromatin by histone modifications. Cell Res 21:381–95 [Google Scholar]
  13. Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y. 13.  et al. 2014. Hypomorphic PCNA mutation underlies a human DNA repair disorder. J. Clin. Investig. 124:3137–46 [Google Scholar]
  14. Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C. 14.  et al. 2004. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am. J. Hum. Genet. 75:27–34 [Google Scholar]
  15. Basten SG, Giles RH. 15.  2013. Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis. Cilia 2:6 [Google Scholar]
  16. Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N. 16.  et al. 2013. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45:1479–82 [Google Scholar]
  17. Beier F, Loeser RF. 17.  2010. Biology and pathology of Rho GTPase, PI-3 kinase-Akt, and MAP kinase signaling pathways in chondrocytes. J. Cell. Biochem. 110:573–80 [Google Scholar]
  18. Below JE, Earl DL, Shively KM, McMillin MJ, Smith JD. 18.  et al. 2013. Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. Am. J. Hum. Genet. 92:137–43 [Google Scholar]
  19. Bhaumik SR, Smith E, Shilatifard A. 19.  2007. Covalent modifications of histones during development and disease pathogenesis. Nat. Struct. Mol. Biol. 14:1008–16 [Google Scholar]
  20. Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J. 20.  et al. 2011. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat. Genet. 43:356–59 [Google Scholar]
  21. Bicknell LS, Walker S, Klingseisen A, Stiff T, Leitch A. 21.  et al. 2011. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat. Genet. 43:350–55 [Google Scholar]
  22. Biesecker L. 22.  2006. The challenges of Proteus syndrome: diagnosis and management. Eur. J. Hum. Genet. 14:1151–57 [Google Scholar]
  23. Bonadio J, Jepsen KJ, Mansoura MK, Jaenisch R, Kuhn JL, Goldstein SA. 23.  1993. A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility. J. Clin. Investig. 92:1697–705 [Google Scholar]
  24. Bongers EM, Opitz JM, Fryer A, Sarda P, Hennekam RC. 24.  et al. 2001. Meier-Gorlin syndrome: report of eight additional cases and review. Am. J. Med. Genet. 102:115–24 [Google Scholar]
  25. Boyden ED, Campos-Xavier AB, Kalamajski S, Cameron TL, Suarez P. 25.  et al. 2011. Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. Am. J. Hum. Genet. 89:767–72 [Google Scholar]
  26. Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A. 26.  et al. 2011. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am. J. Hum. Genet. 89:634–43 [Google Scholar]
  27. Bui C, Huber C, Tuysuz B, Alanay Y, Bole-Feysot C. 27.  et al. 2014. XYLT1 mutations in Desbuquois dysplasia type 2. Am. J. Hum. Genet. 94:405–14 [Google Scholar]
  28. Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman OA. 28.  et al. 2012. Mutations in KAT6B, encoding a histone acetyltransferase, cause genitopatellar syndrome. Am. J. Hum. Genet. 90:282–89 [Google Scholar]
  29. Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L. 29.  et al. 2013. Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am. J. Hum. Genet. 92:781–91 [Google Scholar]
  30. Caux F, Plauchu H, Chibon F, Faivre L, Fain O. 30.  et al. 2007. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur. J. Hum. Genet. 15:767–73 [Google Scholar]
  31. Celli J, van Bokhoven H, Brunner HG. 31.  2003. Feingold syndrome: clinical review and genetic mapping. Am. J. Med. Genet. A 122A:294–300 [Google Scholar]
  32. Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ. 32.  et al. 2012. A single recurrent mutation in the 5′-UTR of IFITM5 causes osteogenesis imperfecta type V. Am. J. Hum. Genet. 91:343–48 [Google Scholar]
  33. Clayton-Smith J, O'Sullivan J, Daly S, Bhaskar S, Day R. 33.  et al. 2011. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am. J. Hum. Genet. 89:675–81 [Google Scholar]
  34. Courtens W, Levi S, Verbelen F, Verloes A, Vamos E. 34.  1997. Feingold syndrome: report of a new family and review. Am. J. Med. Genet. 73:55–60 [Google Scholar]
  35. Dauber A, Lafranchi SH, Maliga Z, Lui JC, Moon JE. 35.  et al. 2012. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J. Clin. Endocrinol. Metab. 97:E2140–51 [Google Scholar]
  36. Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM. 36.  et al. 2011. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat. Genet. 43:189–96 [Google Scholar]
  37. de Munnik SA, Bicknell LS, Aftimos S, Al-Aama JY, van Bever Y. 37.  et al. 2012. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. Eur. J. Hum. Genet. 20:598–606 [Google Scholar]
  38. de Pontual L, Yao E, Callier P, Faivre L, Drouin V. 38.  et al. 2011. Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans. Nat. Genet. 43:1026–30 [Google Scholar]
  39. Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. 39.  1996. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911–21 [Google Scholar]
  40. Dickson LA, Pihlajaniemi T, Deak S, Pope FM, Nicholls A. 40.  et al. 1984. Nuclease S1 mapping of a homozygous mutation in the carboxyl-propeptide-coding region of the proα2(I) collagen gene in a patient with osteogenesis imperfecta. PNAS 81:4524–28 [Google Scholar]
  41. Dighe M, Fligner C, Cheng E, Warren B, Dubinsky T. 41.  2008. Fetal skeletal dysplasia: an approach to diagnosis with illustrative cases. Radiographics 28:1061–77 [Google Scholar]
  42. Dowdle WE, Robinson JF, Kneist A, Sirerol-Piquer MS, Frints SG. 42.  et al. 2011. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am. J. Hum. Genet. 89:94–110 [Google Scholar]
  43. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. 43.  1997. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–54 [Google Scholar]
  44. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J. 44.  et al. 2011. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332:240–43 [Google Scholar]
  45. Favaro FP, Alvizi L, Zechi-Ceide RM, Bertola D, Felix TM. 45.  et al. 2014. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects. Am. J. Hum. Genet. 94:120–28 [Google Scholar]
  46. Feingold M, Hall BD, Lacassie Y, Martinez-Frias ML. 46.  1997. Syndrome of microcephaly, facial and hand abnormalities, tracheoesophageal fistula, duodenal atresia, and developmental delay. Am. J. Med. Genet. 69:245–49 [Google Scholar]
  47. Ford-Hutchinson AF, Ali Z, Lines SE, Hallgrimsson B, Boyd SK, Jirik FR. 47.  2007. Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth. J. Bone Miner. Res. 22:1245–59 [Google Scholar]
  48. Francomano CA, Liberfarb RM, Hirose T, Maumenee IH, Streeten EA. 48.  et al. 1987. The Stickler syndrome: evidence for close linkage to the structural gene for type II collagen. Genomics 1:293–96 [Google Scholar]
  49. Francomano CA, Ortiz de Luna RI, Hefferon TW, Bellus GA, Turner CE. 49.  et al. 1994. Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p. Hum. Mol. Genet. 3:787–92 [Google Scholar]
  50. Fry AM, O'Regan L, Sabir SR, Bayliss R. 50.  2012. Cell cycle regulation by the NEK family of protein kinases. J. Cell Sci. 125:4423–33 [Google Scholar]
  51. Gao B, Song H, Bishop K, Elliot G, Garrett L. 51.  et al. 2011. Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev. Cell 20:163–76 [Google Scholar]
  52. Garbes L, Kim K, Riess A, Hoyer-Kuhn H, Beleggia F. 52.  et al. 2015. Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. Am. J. Hum. Genet. 96:432–39 [Google Scholar]
  53. Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X. 53.  et al. 2013. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci. Transl. Med. 5:203ra124 [Google Scholar]
  54. Geister KA, Brinkmeier ML, Hsieh M, Faust SM, Karolyi IJ. 54.  et al. 2013. A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type. Hum. Mol. Genet. 22:345–57 [Google Scholar]
  55. Glazov EA, Zankl A, Donskoi M, Kenna TJ, Thomas GP. 55.  et al. 2011. Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLOS Genet. 7:e1002027 [Google Scholar]
  56. Goetz SC, Anderson KV. 56.  2010. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11:331–44 [Google Scholar]
  57. Goriely A, Wilkie AO. 57.  2012. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90:175–200 [Google Scholar]
  58. Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T. 58.  et al. 2008. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat. Genet. 40:232–36 [Google Scholar]
  59. Grosch M, Grüner B, Spranger S, Stütz A, Rausch T. 59.  et al. 2013. Identification of a ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype. Matrix Biol. 32:387–92 [Google Scholar]
  60. 60. Growth Horm. Res. Soc 2000. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J. Clin. Endocrinol. Metab. 85:3990–93 [Google Scholar]
  61. Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C. 61.  et al. 2011. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nat. Genet. 43:360–64 [Google Scholar]
  62. Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA. 62.  et al. 2013. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am. J. Hum. Genet. 93:915–25 [Google Scholar]
  63. Happle R. 63.  1987. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J. Am. Acad. Dermatol. 16:899–906 [Google Scholar]
  64. He H, Liyanarachchi S, Akagi K, Nagy R, Li J. 64.  et al. 2011. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332:238–40 [Google Scholar]
  65. Hemerly AS, Prasanth SG, Siddiqui K, Stillman B. 65.  2009. Orc1 controls centriole and centrosome copy number in human cells. Science 323:789–93 [Google Scholar]
  66. Hiramatsu K, Sasagawa S, Outani H, Nakagawa K, Yoshikawa H, Tsumaki N. 66.  2011. Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. J. Clin. Investig. 121:640–57 [Google Scholar]
  67. Hirata M, Kugimiya F, Fukai A, Ohba S, Kawamura N. 67.  et al. 2009. C/EBPβ promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57Kip2. PLOS ONE 4:e4543 [Google Scholar]
  68. Hoover-Fong J, Sobreira N, Jurgens J, Modaff P, Blout C. 68.  et al. 2014. Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am. J. Hum. Genet. 94:105–12 [Google Scholar]
  69. Horton WA, Hall JG, Hecht JT. 69.  2007. Achondroplasia. Lancet 370:162–72 [Google Scholar]
  70. Hossain M, Stillman B. 70.  2012. Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication. Genes Dev. 26:1797–810 [Google Scholar]
  71. Hsieh SC, Chen NT, Lo SH. 71.  2009. Conditional loss of PTEN leads to skeletal abnormalities and lipoma formation. Mol. Carcinog. 48:545–52 [Google Scholar]
  72. Huber C, Cormier-Daire V. 72.  2012. Ciliary disorder of the skeleton. Am. J. Med. Genet. C 160C:165–74 [Google Scholar]
  73. Huber C, Faqeih EA, Bartholdi D, Bole-Feysot C, Borochowitz Z. 73.  et al. 2013. Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia. Am. J. Hum. Genet. 92:144–49 [Google Scholar]
  74. Huber C, Wu S, Kim AS, Sigaudy S, Sarukhanov A. 74.  et al. 2013. WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia. Am. J. Hum. Genet. 93:926–31 [Google Scholar]
  75. Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T. 75.  et al. 2011. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development 138:1507–19 [Google Scholar]
  76. Ishikawa H, Marshall WF. 76.  2011. Ciliogenesis: building the cell's antenna. Nat. Rev. Mol. Cell Biol. 12:222–34 [Google Scholar]
  77. Jin M, Yu Y, Qi H, Xie Y, Su N. 77.  et al. 2012. A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Hum. Mol. Genet. 21:5443–55 [Google Scholar]
  78. Jonquoy A, Mugniery E, Benoist-Lasselin C, Kaci N, Le Corre L. 78.  et al. 2012. A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. Hum. Mol. Genet. 21:841–51 [Google Scholar]
  79. Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E. 79.  et al. 2011. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat. Genet. 43:23–26 [Google Scholar]
  80. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL. 80.  et al. 1994. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8:277–89 [Google Scholar]
  81. Karsenty G, Kronenberg HM, Settembre C. 81.  2009. Genetic control of bone formation. Annu. Rev. Cell Dev. Biol. 25:629–48 [Google Scholar]
  82. Kawasaki Y, Kugimiya F, Chikuda H, Kamekura S, Ikeda T. 82.  et al. 2008. Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes. J. Clin. Investig. 118:2506–15 [Google Scholar]
  83. Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M. 83.  et al. 2013. Mutations in WNT1 cause different forms of bone fragility. Am. J. Hum. Genet. 92:565–74 [Google Scholar]
  84. Klingseisen A, Jackson AP. 84.  2011. Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev. 25:2011–24 [Google Scholar]
  85. Knoblich JA. 85.  2010. Asymmetric cell division: recent developments and their implications for tumour biology. Nat. Rev. Mol. Cell Biol. 11:849–60 [Google Scholar]
  86. Krakow D, Rimoin DL. 86.  2010. The skeletal dysplasias. Genet Med. 12:327–41 [Google Scholar]
  87. Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M. 87.  et al. 2005. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J. Cell Sci. 118:5089–100 [Google Scholar]
  88. Kronenberg HM. 88.  2003. Developmental regulation of the growth plate. Nature 423:332–36 [Google Scholar]
  89. Kronenberg HM. 89.  2006. PTHrP and skeletal development. Ann. N.Y. Acad. Sci. 1068:1–13 [Google Scholar]
  90. Kuo AJ, Song J, Cheung P, Ishibe-Murakami S, Yamazoe S. 90.  et al. 2012. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484:115–19 [Google Scholar]
  91. Lachman RS, Tiller GE, Graham JM Jr, Rimoin DL. 91.  1992. Collagen, genes and the skeletal dysplasias on the edge of a new era: a review and update. Eur. J. Radiol. 14:1–10 [Google Scholar]
  92. Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN. 92.  et al. 2010. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–38 [Google Scholar]
  93. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V. 93.  et al. 2012. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat. Genet. 44:85–88 [Google Scholar]
  94. Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A. 94.  et al. 2011. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am. J. Hum. Genet. 89:7–14 [Google Scholar]
  95. Le Merrer M, Rousseau F, Legeai-Mallet L, Landais JC, Pelet A. 95.  et al. 1994. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nat. Genet. 6:318–21 [Google Scholar]
  96. Lee B, Thirunavukkarasu K, Zhou L, Pastore L, Baldini A. 96.  et al. 1997. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat. Genet. 16:307–10 [Google Scholar]
  97. Lee B, Vissing H, Ramirez F, Rogers D, Rimoin D. 97.  1989. Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science 244:978–80 [Google Scholar]
  98. Lee H, Graham JM Jr, Rimoin DL, Lachman RS, Krejci P. 98.  et al. 2012. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90:746–51 [Google Scholar]
  99. Li Y, Dudley AT. 99.  2009. Noncanonical frizzled signaling regulates cell polarity of growth plate chondrocytes. Development 136:1083–92 [Google Scholar]
  100. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM. 100.  et al. 2011. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365:611–19 [Google Scholar]
  101. Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y. 101.  et al. 2011. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N. Engl. J. Med. 364:2218–26 [Google Scholar]
  102. Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E. 102.  et al. 2012. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am. J. Hum. Genet. 91:1108–14 [Google Scholar]
  103. Marini JC, Blissett AR. 103.  2013. New genes in bone development: what's new in osteogenesis imperfecta. J. Clin. Endocrinol. Metab. 98:3095–103 [Google Scholar]
  104. Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS. 104.  et al. 2014. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat. Genet. 46:1283–92 [Google Scholar]
  105. Martinez-Glez V, Valencia M, Caparros-Martin JA, Aglan M, Temtamy S. 105.  et al. 2012. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum. Mutat. 33:343–50 [Google Scholar]
  106. Matsushita M, Kitoh H, Ohkawara B, Mishima K, Kaneko H. 106.  et al. 2013. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLOS ONE 8:e81569 [Google Scholar]
  107. McInerney-Leo AM, Schmidts M, Cortes CR, Leo PJ, Gener B. 107.  et al. 2013. Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. Am. J. Hum. Genet. 93:515–23 [Google Scholar]
  108. Mehawej C, Delahodde A, Legeai-Mallet L, Delague V, Kaci N. 108.  et al. 2014. The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. PLOS Genet. 10:e1004311 [Google Scholar]
  109. Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N. 109.  et al. 2012. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am. J. Hum. Genet. 90:550–57 [Google Scholar]
  110. Metzker ML. 110.  2010. Sequencing technologies—the next generation. Nat. Rev. Genet. 11:31–46 [Google Scholar]
  111. Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C. 111.  et al. 2012. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90:740–45 [Google Scholar]
  112. Mill P, Lockhart PJ, Fitzpatrick E, Mountford HS, Hall EA. 112.  et al. 2011. Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am. J. Hum. Genet. 88:508–15 [Google Scholar]
  113. Min BJ, Kim N, Chung T, Kim OH, Nishimura G. 113.  et al. 2011. Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. Am. J. Hum. Genet. 89:760–66 [Google Scholar]
  114. Mirzaa GM, Vitre B, Carpenter G, Abramowicz I, Gleeson JG. 114.  et al. 2014. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum. Genet. 133:1023–39 [Google Scholar]
  115. Moens CB, Auerbach AB, Conlon RA, Joyner AL, Rossant J. 115.  1992. A targeted mutation reveals a role for N-myc in branching morphogenesis in the embryonic mouse lung. Genes Dev. 6:691–704 [Google Scholar]
  116. Mohamed JY, Faqeih E, Alsiddiky A, Alshammari MJ, Ibrahim NA, Alkuraya FS. 116.  2013. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am. J. Hum. Genet. 92:157–61 [Google Scholar]
  117. Muenzer J. 117.  2014. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol. Genet. Metab. 111:63–72 [Google Scholar]
  118. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS. 118.  et al. 1997. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–79 [Google Scholar]
  119. Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, de Crombrugghe B. 119.  2004. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes Dev. 18:290–305 [Google Scholar]
  120. Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q. 120.  et al. 2015. Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am. J. Hum. Genet. 96:412–24 [Google Scholar]
  121. Nagy A, Moens C, Ivanyi E, Pawling J, Gertsenstein M. 121.  et al. 1998. Dissecting the role of N-myc in development using a single targeting vector to generate a series of alleles. Curr. Biol. 8:661–64 [Google Scholar]
  122. Nicole S, Davoine CS, Topaloglu H, Cattolico L, Barral D. 122.  et al. 2000. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat. Genet. 26:480–83 [Google Scholar]
  123. Nigg EA, Stearns T. 123.  2011. The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nat. Cell Biol. 13:1154–60 [Google Scholar]
  124. Nundlall S, Rajpar MH, Bell PA, Clowes C, Zeeff LA. 124.  et al. 2010. An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia. Cell Stress Chaperones 15:835–49 [Google Scholar]
  125. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. 125.  2003. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat. Genet. 33:497–501 [Google Scholar]
  126. Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S. 126.  et al. 2012. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome. PLOS Genet. 8:e1002945 [Google Scholar]
  127. Okada M, Ikegawa S, Morioka M, Yamashita A, Saito A. 127.  et al. 2015. Modeling type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cells. Hum. Mol. Genet. 24:299–313 [Google Scholar]
  128. Ota S, Zhou ZQ, Keene DR, Knoepfler P, Hurlin PJ. 128.  2007. Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Development 134:1583–92 [Google Scholar]
  129. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC. 129.  et al. 1997. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–71 [Google Scholar]
  130. Outani H, Okada M, Hiramatsu K, Yoshikawa H, Tsumaki N. 130.  2011. Induction of chondrogenic cells from dermal fibroblast culture by defined factors does not involve a pluripotent state. Biochem. Biophys. Res. Commun. 411:607–12 [Google Scholar]
  131. Outani H, Okada M, Yamashita A, Nakagawa K, Yoshikawa H, Tsumaki N. 131.  2013. Direct induction of chondrogenic cells from human dermal fibroblast culture by defined factors. PLOS ONE 8:e77365 [Google Scholar]
  132. Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML. 132.  et al. 2011. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat. Genet. 43:1256–61 [Google Scholar]
  133. Payne F, Colnaghi R, Rocha N, Seth A, Harris J. 133.  et al. 2014. Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance. J. Clin. Investig. 124:4028–38 [Google Scholar]
  134. Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA. 134.  et al. 2012. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am. J. Hum. Genet. 90:864–70 [Google Scholar]
  135. Piel M, Meyer P, Khodjakov A, Rieder CL, Bornens M. 135.  2000. The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J. Cell Biol. 149:317–30 [Google Scholar]
  136. Pihlajaniemi T, Dickson LA, Pope FM, Korhonen VR, Nicholls A. 136.  et al. 1984. Osteogenesis imperfecta: cloning of a pro-α2(I) collagen gene with a frameshift mutation. J. Biol. Chem. 259:12941–44 [Google Scholar]
  137. Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ. 137.  et al. 2011. CtIP mutations cause Seckel and Jawad syndromes. PLOS Genet. 7:e1002310 [Google Scholar]
  138. Rajpar MH, McDermott B, Kung L, Eardley R, Knowles L. 138.  et al. 2009. Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLOS Genet. 5:e1000691 [Google Scholar]
  139. Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ. 139.  et al. 2008. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319:816–19 [Google Scholar]
  140. Rios JJ, Paria N, Burns DK, Israel BA, Cornelia R. 140.  et al. 2013. Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum. Mol. Genet. 22:444–51 [Google Scholar]
  141. Romereim SM, Conoan NH, Chen B, Dudley AT. 141.  2014. A dynamic cell adhesion surface regulates tissue architecture in growth plate cartilage. Development 141:2085–95 [Google Scholar]
  142. Romereim SM, Dudley AT. 142.  2011. Cell polarity: the missing link in skeletal morphogenesis?. Organogenesis 7:217–28 [Google Scholar]
  143. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM. 143.  et al. 1994. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–54 [Google Scholar]
  144. Sarig O, Nahum S, Rapaport D, Ishida-Yamamoto A, Fuchs-Telem D. 144.  et al. 2012. Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome is caused by a POC1A mutation. Am. J. Hum. Genet. 91:337–42 [Google Scholar]
  145. Savarirayan R, Rimoin DL. 145.  2002. The skeletal dysplasias. Best Pract. Res. Clin. Endocrinol. Metab. 16:547–60 [Google Scholar]
  146. Schmidts M, Vodopiutz J, Christou-Savina S, Cortes CR, McInerney-Leo AM. 146.  et al. 2013. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 93:932–44 [Google Scholar]
  147. Schreml J, Durmaz B, Cogulu O, Keupp K, Beleggia F. 147.  et al. 2014. The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum. Genet. 133:29–39 [Google Scholar]
  148. Semler O, Garbes L, Keupp K, Swan D, Zimmermann K. 148.  et al. 2012. A mutation in the 5′-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am. J. Hum. Genet. 91:349–57 [Google Scholar]
  149. Shaheen R, Al Tala S, Almoisheer A, Alkuraya FS. 149.  2014. Mutation in PLK4, encoding a master regulator of centriole formation, defines a novel locus for primordial dwarfism. J. Med. Genet. 51:814–16 [Google Scholar]
  150. Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N. 150.  et al. 2012. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J. Med. Genet. 49:630–35 [Google Scholar]
  151. Shaheen R, Faqeih E, Shamseldin HE, Noche RR, Sunker A. 151.  et al. 2012. POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism. Am. J. Hum. Genet. 91:330–36 [Google Scholar]
  152. Shaheen R, Schmidts M, Faqeih E, Hashem A, Lausch E. 152.  et al. 2015. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies. Hum. Mol. Genet. 24:1410–19 [Google Scholar]
  153. Shaheen R, Shamseldin HE, Loucks CM, Seidahmed MZ, Ansari S. 153.  et al. 2014. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am. J. Hum. Genet. 94:73–79 [Google Scholar]
  154. Shamseldin HE, Rajab A, Alhashem A, Shaheen R, Al-Shidi T. 154.  et al. 2013. Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome. Am. J. Hum. Genet. 93:555–60 [Google Scholar]
  155. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ. 155.  et al. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–42 [Google Scholar]
  156. Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX. 156.  2007. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet. 39:1145–50 [Google Scholar]
  157. Smits P, Bolton AD, Funari V, Hong M, Boyden ED. 157.  et al. 2010. Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. N. Engl. J. Med. 362:206–16 [Google Scholar]
  158. Song B, Haycraft CJ, Seo HS, Yoder BK, Serra R. 158.  2007. Development of the post-natal growth plate requires intraflagellar transport proteins. Dev. Biol. 305:202–16 [Google Scholar]
  159. Stiff T, Alagoz M, Alcantara D, Outwin E, Brunner HG. 159.  et al. 2013. Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome. PLOS Genet. 9:e1003360 [Google Scholar]
  160. Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee SJ. 160.  1994. Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily. Nature 368:639–43 [Google Scholar]
  161. Stray-Pedersen A, Backe PH, Sorte HS, Morkrid L, Chokshi NY. 161.  et al. 2014. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am. J. Hum. Genet. 95:96–107 [Google Scholar]
  162. Symoens S, Malfait F, D'Hondt S, Callewaert B, Dheedene A. 162.  et al. 2013. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J. Rare Dis. 8:154 [Google Scholar]
  163. Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA. 163.  et al. 2011. NEK1 mutations cause short-rib polydactyly syndrome type Majewski. Am. J. Hum. Genet. 88:106–14 [Google Scholar]
  164. Thomas S, Legendre M, Saunier S, Bessieres B, Alby C. 164.  et al. 2012. TCTN3 mutations cause Mohr-Majewski syndrome. Am. J. Hum. Genet. 91:372–78 [Google Scholar]
  165. Tsang KY, Chan D, Cheslett D, Chan WC, So CL. 165.  et al. 2007. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLOS Biol. 5:e44 [Google Scholar]
  166. Tsipouras P, Myers JC, Ramirez F, Prockop DJ. 166.  1983. Restriction fragment length polymorphism associated with the proα2(I) gene of human type I procollagen: application to a family with an autosomal dominant form of osteogenesis imperfecta. J. Clin. Investig. 72:1262–67 [Google Scholar]
  167. Tunkel D, Alade Y, Kerbavaz R, Smith B, Rose-Hardison D, Hoover-Fong J. 167.  2012. Hearing loss in skeletal dysplasia patients. Am. J. Med. Genet. A 158A:1551–55 [Google Scholar]
  168. Tuz K, Bachmann-Gagescu R, O'Day DR, Hua K, Isabella CR. 168.  et al. 2014. Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 94:62–72 [Google Scholar]
  169. Ulici V, James CG, Hoenselaar KD, Beier F. 169.  2010. Regulation of gene expression by PI3K in mouse growth plate chondrocytes. PLOS ONE 5:e8866 [Google Scholar]
  170. Unlu G, Levic DS, Melville DB, Knapik EW. 170.  2014. Trafficking mechanisms of extracellular matrix macromolecules: insights from vertebrate development and human diseases. Int. J. Biochem. Cell Biol. 47:57–67 [Google Scholar]
  171. Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL. 171.  et al. 2010. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat. Genet. 42:619–25 [Google Scholar]
  172. van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B. 172.  et al. 2005. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat. Genet. 37:465–67 [Google Scholar]
  173. Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI Jr, Gusella JF, Tsipouras P. 173.  1994. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nat. Genet. 6:314–17 [Google Scholar]
  174. Venoux M, Tait X, Hames RS, Straatman KR, Woodland HR, Fry AM. 174.  2013. Poc1A and Poc1B act together in human cells to ensure centriole integrity. J. Cell Sci. 126:163–75 [Google Scholar]
  175. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A. 175.  et al. 2008. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132:875–86 [Google Scholar]
  176. Vilain E, Le Merrer M, Lecointre C, Desangles F, Kay MA. 176.  et al. 1999. IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. J. Clin. Endocrinol. Metab. 84:4335–40 [Google Scholar]
  177. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ. 177.  1996. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–22 [Google Scholar]
  178. Wallingford JB, Mitchell B. 178.  2011. Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. Genes Dev. 25:201–13 [Google Scholar]
  179. Wang B, Sinha T, Jiao K, Serra R, Wang J. 179.  2011. Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. Hum. Mol. Genet. 20:271–85 [Google Scholar]
  180. Wang X, Tsai JW, Imai JH, Lian WN, Vallee RB, Shi SH. 180.  2009. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461:947–55 [Google Scholar]
  181. Wang Y, Wysocka J, Perlin JR, Leonelli L, Allis CD, Coonrod SA. 181.  2004. Linking covalent histone modifications to epigenetics: the rigidity and plasticity of the marks. Cold Spring Harb. Symp. Quant. Biol. 69:161–69 [Google Scholar]
  182. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R. 182.  et al. 2011. Nosology and classification of genetic skeletal disorders: 2010 revision. Am. J. Med. Genet. A 155A:943–68 [Google Scholar]
  183. Webster MK, D'Avis PY, Robertson SC, Donoghue DJ. 183.  1996. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol. Cell. Biol. 16:4081–87 [Google Scholar]
  184. Webster MK, Donoghue DJ. 184.  1996. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 15:520–27 [Google Scholar]
  185. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. 185.  1991. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 325:1688–95 [Google Scholar]
  186. Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM. 186.  et al. 2015. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J. Pharmacol. Exp. Ther. 353:132–49 [Google Scholar]
  187. Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G. 187.  et al. 2010. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87:219–28 [Google Scholar]
  188. Wood AR, Esko T, Yang J, Vedantam S, Pers TH. 188.  et al. 2014. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46:1173–86 [Google Scholar]
  189. Xie Y, Su N, Jin M, Qi H, Yang J. 189.  et al. 2012. Intermittent PTH (1–34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum. Mol. Genet. 21:3941–55 [Google Scholar]
  190. Yamamoto GL, Baratela WA, Almeida TF, Lazar M, Afonso CL. 190.  et al. 2014. Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am. J. Hum. Genet. 94:113–19 [Google Scholar]
  191. Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y. 191.  et al. 2014. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 513:507–11 [Google Scholar]
  192. Yang G, Sun Q, Teng Y, Li F, Weng T, Yang X. 192.  2008. PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress. Development 135:3587–97 [Google Scholar]
  193. Yang G, Zhu L, Hou N, Lan Y, Wu XM. 193.  et al. 2014. Osteogenic fate of hypertrophic chondrocytes. Cell Res. 24:1266–69 [Google Scholar]
  194. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. 194.  2014. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. PNAS 111:12097–102 [Google Scholar]
  195. Yasoda A, Kitamura H, Fujii T, Kondo E, Murao N. 195.  et al. 2009. Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 150:3138–44 [Google Scholar]
  196. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A. 196.  et al. 2004. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat. Med. 10:80–86 [Google Scholar]
  197. Yasoda A, Nakao K. 197.  2010. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr. J. 57:659–66 [Google Scholar]
  198. Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. 198.  2014. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLOS Genet. 10:e1004820 [Google Scholar]
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