Dominant-negative SOX9 Mutations in Campomelic Dysplasia

Overview

Journal Hum Mutat

Specialty Genetics

Date 2019 Aug 8

PMID 31389106

Citations 14

Authors

Fabiana Csukasi

Ivan Duran

Wenjuan Zhang

Jorge H Martin

Maya Barad

Michael Bamshad

Mary Ann Weis

David Eyre

Deborah Krakow

Daniel H Cohn

Affiliations

Soon will be listed here.

Abstract

Campomelic dysplasia (CD) is an autosomal dominant, perinatal lethal skeletal dysplasia characterized by a small chest and short long bones with bowing of the lower extremities. CD is the result of heterozygosity for mutations in the gene encoding the chondrogenesis master regulator, SOX9. Loss-of-function mutations have been identified in most CD cases so it has been assumed that the disease results from haploinsufficiency for SOX9. Here, we identified distal truncating SOX9 mutations in four unrelated CD cases. The mutations all leave the dimerization and DNA-binding domains intact and cultured chondrocytes from three of the four cases synthesized truncated SOX9. Relative to CD resulting from haploinsufficiency, there was decreased transactivation activity toward a major transcriptional target, COL2A1, consistent with the mutations exerting a dominant-negative effect. For one of the cases, the phenotypic consequence was a very severe form of CD, with a pronounced effect on vertebral and limb development. The data identify a novel molecular mechanism of disease in CD in which the truncated protein leads to a distinct and more significant effect on SOX9 function.

Citing Articles

The Expression Level of SOX Family Transcription Factors' mRNA as a Diagnostic Marker for Osteoarthritis.

Baran K, Brzezianska-Lasota E, Kryczka J, Boncela J, Czechowska A, Kopacz K J Clin Med. 2025; 14(4).

PMID: 40004707 PMC: 11856735. DOI: 10.3390/jcm14041176.

Variants in the SOX9 transactivation middle domain induce axial skeleton dysplasia and scoliosis.

Wang L, Liu Z, Zhao S, Xu K, Aceves V, Qiu C Proc Natl Acad Sci U S A. 2025; 122(4):e2313978121.

PMID: 39854231 PMC: 11789016. DOI: 10.1073/pnas.2313978121.

Modeling vascular dynamics at the initial stage of endochondral ossification on a microfluidic chip using a human embryonic-stem-cell-derived organoid.

Kesharwani A, Tani S, Nishikawa M, Sakai Y, Okada H, Ohba S Regen Ther. 2024; 28:90-100.

PMID: 39703814 PMC: 11655692. DOI: 10.1016/j.reth.2024.11.018.

NSAID-mediated cyclooxygenase inhibition disrupts ectodermal derivative formation in axolotl embryos.

Marshall E, Ramarapu R, Leathers T, Morrison-Welch N, Sandberg K, Kawashima M bioRxiv. 2024; .

PMID: 39554061 PMC: 11565853. DOI: 10.1101/2024.10.30.621122.

Dissecting SOX9 dynamics reveals its differential regulation in osteoarthritis.

Govindaraj K, Kannan S, Coutinho de Almeida R, Jansen Klomp L, Karperien M, Meulenbelt I J Cell Physiol. 2024; 239(12):e31443.

PMID: 39344191 PMC: 11649970. DOI: 10.1002/jcp.31443.

References

Sivaraj K, Adams R . Blood vessel formation and function in bone. Development. 2016; 143(15):2706-15. DOI: 10.1242/dev.136861. View

Mansour S, Hall C, Pembrey M, Young I . A clinical and genetic study of campomelic dysplasia. J Med Genet. 1995; 32(6):415-20. PMC: 1050480. DOI: 10.1136/jmg.32.6.415. View

Meyer J, Sudbeck P, Held M, Wagner T, Schmitz M, Bricarelli F . Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum Mol Genet. 1997; 6(1):91-8. DOI: 10.1093/hmg/6.1.91. View

Akiyama H, Chaboissier M, Martin J, Schedl A, de Crombrugghe B . The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002; 16(21):2813-28. PMC: 187468. DOI: 10.1101/gad.1017802. View

Vissing H, DAlessio M, Lee B, Ramirez F, Godfrey M, Hollister D . Glycine to serine substitution in the triple helical domain of pro-alpha 1 (II) collagen results in a lethal perinatal form of short-limbed dwarfism. J Biol Chem. 1989; 264(31):18265-7. View

Nakamura Y, Yamamoto K, He X, Otsuki B, Kim Y, Murao H . Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun. 2011; 2:251. PMC: 4040945. DOI: 10.1038/ncomms1242. View

Gentilin B, Forzano F, Bedeschi M, Rizzuti T, Faravelli F, Izzi C . Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene. Ultrasound Obstet Gynecol. 2010; 36(3):315-23. DOI: 10.1002/uog.7761. View

Velagaleti G, Bien-Willner G, Northup J, Lockhart L, Hawkins J, Jalal S . Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet. 2005; 76(4):652-62. PMC: 1199302. DOI: 10.1086/429252. View

Lefebvre V, Dvir-Ginzberg M . SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect Tissue Res. 2016; 58(1):2-14. PMC: 5287363. DOI: 10.1080/03008207.2016.1183667. View

10.

Lee H, Graham Jr J, Rimoin D, Lachman R, Krejci P, Tompson S . Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet. 2012; 90(4):746-51. PMC: 3322224. DOI: 10.1016/j.ajhg.2012.03.004. View

11.

Stoeva R, Grozdanova L, Scherer G, Krasteva M, Bausch E, Krastev T . A novel SOX9 nonsense mutation, q401x, in a case of campomelic dysplasia with XY sex reversal. Genet Couns. 2011; 22(1):49-53. View

12.

FOSTER J, Guioli S, Kwok C, Weller P, Stevanovic M, Weissenbach J . Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994; 372(6506):525-30. DOI: 10.1038/372525a0. View

13.

Ohba S, He X, Hojo H, McMahon A . Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte. Cell Rep. 2015; 12(2):229-43. PMC: 4504750. DOI: 10.1016/j.celrep.2015.06.013. View

14.

Kozhemyakina E, Lassar A, Zelzer E . A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015; 142(5):817-31. PMC: 4352987. DOI: 10.1242/dev.105536. View

15.

Bi W, Huang W, Whitworth D, Deng J, Zhang Z, Behringer R . Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci U S A. 2001; 98(12):6698-703. PMC: 34415. DOI: 10.1073/pnas.111092198. View

16.

BOGAERT R, Tiller G, Weis M, Gruber H, Rimoin D, Cohn D . An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis. J Biol Chem. 1992; 267(31):22522-6. View

17.

Kwok C, Weller P, Guioli S, FOSTER J, Mansour S, Zuffardi O . Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Am J Hum Genet. 1995; 57(5):1028-36. PMC: 1801368. View

18.

Liu Y, Li H, Tanaka K, Tsumaki N, Yamada Y . Identification of an enhancer sequence within the first intron required for cartilage-specific transcription of the alpha2(XI) collagen gene. J Biol Chem. 2000; 275(17):12712-8. DOI: 10.1074/jbc.275.17.12712. View

19.

Lefebvre V, Huang W, Harley V, Goodfellow P, de Crombrugghe B . SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol. 1997; 17(4):2336-46. PMC: 232082. DOI: 10.1128/MCB.17.4.2336. View

20.

Bell D, Leung K, Wheatley S, Ng L, Zhou S, Ling K . SOX9 directly regulates the type-II collagen gene. Nat Genet. 1997; 16(2):174-8. DOI: 10.1038/ng0697-174. View