Dominant-negative SOX9 mutations in campomelic dysplasia.

Autor: Csukasi F; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California., Duran I; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California., Zhang W; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California.; Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California.; Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California., Martin JH; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California., Barad M; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California., Bamshad M; Department of Genome Sciences, University of Washington, Seattle, Washington.; Department of Pediatrics, University of Washington, Seattle, Washington.; University of Washington Center for Mendelian Genomics, Seattle, Washington., Weis MA; Department of Orthopaedic Surgery, University of Washington, Seattle, Washington., Eyre D; Department of Orthopaedic Surgery, University of Washington, Seattle, Washington., Krakow D; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California.; Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California.; Department of Human Genetics, University of California Los Angeles, Los Angeles, California.; Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California., Cohn DH; Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California.; Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California.; Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2019 Dec; Vol. 40 (12), pp. 2344-2352. Date of Electronic Publication: 2019 Aug 26.
DOI: 10.1002/humu.23888
Abstrakt: 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.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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