Functional and structural studies of wild SOX9 and mutations causing campomelic dysplasia

Sharon McDowall, Anthony Argentaro, Shoba Ranganathan, Polly Weller, Sabine Mertin, Sahar Mansour, John Tolmie, Vincent Harley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

In humans, mutations in SOX9 result in a skeletal malformation syndrome, campomelic dysplasia (CD). The present study investigated two major classes of CD mutations: 1) point mutations in the high mobility group (HMG) domain and 2) truncations and frameshifts that alter the C terminus of the protein. We analyzed the effect of one novel mutation and three other point mutations in the HMG domain of SOX9 on the DNA binding and DNA bending properties of the protein. The F12L mutant HMG domain shows negligible DNA binding, the H65Y mutant shows minimal DNA binding, whereas the A19V mutant shows near wild type DNA binding and bends DNA normally. Interestingly, the P70R mutant has altered DNA binding specificity, but also bends DNA normally. The effects of the point mutations were interpreted using a molecular model of the SOX9 HMG domain. We analyzed the effects upon transcription of mutations resembling the truncation and frameshift mutations in CD patients, and found that progressive deletion of the C terminus causes progressive loss of transactivation. Maximal transactivation by SOX9 requires both the C-terminal domain rich in proline, glutamine, and serine and the adjacent domain composed entirely of proline, glutamine, and alanine. Thus, CD arises by mutations that interfere with DNA binding by SOX9 or truncate the C-terminal transactivation domain and thereby impede the ability of SOX9 to activate target genes during organ development.

LanguageEnglish
Pages24023-24030
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number34
DOIs
Publication statusPublished - 20 Aug 1999
Externally publishedYes

Fingerprint

Campomelic Dysplasia
Mutation
DNA
Point Mutation
Transcriptional Activation
Glutamine
Proline
Frameshift Mutation
Molecular Models
Transcription
Protein C
Alanine
Serine
Proteins
Genes

Cite this

McDowall, Sharon ; Argentaro, Anthony ; Ranganathan, Shoba ; Weller, Polly ; Mertin, Sabine ; Mansour, Sahar ; Tolmie, John ; Harley, Vincent. / Functional and structural studies of wild SOX9 and mutations causing campomelic dysplasia. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 34. pp. 24023-24030.
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abstract = "In humans, mutations in SOX9 result in a skeletal malformation syndrome, campomelic dysplasia (CD). The present study investigated two major classes of CD mutations: 1) point mutations in the high mobility group (HMG) domain and 2) truncations and frameshifts that alter the C terminus of the protein. We analyzed the effect of one novel mutation and three other point mutations in the HMG domain of SOX9 on the DNA binding and DNA bending properties of the protein. The F12L mutant HMG domain shows negligible DNA binding, the H65Y mutant shows minimal DNA binding, whereas the A19V mutant shows near wild type DNA binding and bends DNA normally. Interestingly, the P70R mutant has altered DNA binding specificity, but also bends DNA normally. The effects of the point mutations were interpreted using a molecular model of the SOX9 HMG domain. We analyzed the effects upon transcription of mutations resembling the truncation and frameshift mutations in CD patients, and found that progressive deletion of the C terminus causes progressive loss of transactivation. Maximal transactivation by SOX9 requires both the C-terminal domain rich in proline, glutamine, and serine and the adjacent domain composed entirely of proline, glutamine, and alanine. Thus, CD arises by mutations that interfere with DNA binding by SOX9 or truncate the C-terminal transactivation domain and thereby impede the ability of SOX9 to activate target genes during organ development.",
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McDowall, S, Argentaro, A, Ranganathan, S, Weller, P, Mertin, S, Mansour, S, Tolmie, J & Harley, V 1999, 'Functional and structural studies of wild SOX9 and mutations causing campomelic dysplasia', Journal of Biological Chemistry, vol. 274, no. 34, pp. 24023-24030. https://doi.org/10.1074/jbc.274.34.24023

Functional and structural studies of wild SOX9 and mutations causing campomelic dysplasia. / McDowall, Sharon; Argentaro, Anthony; Ranganathan, Shoba; Weller, Polly; Mertin, Sabine; Mansour, Sahar; Tolmie, John; Harley, Vincent.

In: Journal of Biological Chemistry, Vol. 274, No. 34, 20.08.1999, p. 24023-24030.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Functional and structural studies of wild SOX9 and mutations causing campomelic dysplasia

AU - McDowall, Sharon

AU - Argentaro, Anthony

AU - Ranganathan, Shoba

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AU - Mansour, Sahar

AU - Tolmie, John

AU - Harley, Vincent

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