Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.
نویسندگان
چکیده
Campomelic dysplasia (CD) is a semilethal osteochondrodysplasia, characterized by skeletal anomalies that include bending of the long bones, and by XY sex reversal. CD results from haploinsufficiency for the transcription factor SOX9, a key regulator at various steps of cartilage differentiation and of early testis development. Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain. We present two CD patients with de novo mutations in a conserved region preceding the HMG domain. A long-term survivor with the acampomelic form of CD has an A76E amino acid substitution, while a severely affected CD patient had an in-frame deletion of amino acid residues 66-75. The conserved domain has been shown to function in the related transcription factor SOX10 as a DNA-dependent dimerization domain. We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap. Dimerization and the resulting capacity to activate promoters via dimeric binding sites is lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. These findings establish the dimerization domain as the third domain essential for SOX9 function during chondrogenesis.
منابع مشابه
The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template
Mutations in SOX9, a gene essential for chondrocyte differentiation cause the human disease campomelic dysplasia (CD). To understand how SOX9 activates transcription, we characterized the DNA binding and cell-free transcription ability of wild-type SOX9 and a dimerization domain SOX9 mutant. Whereas formation of monomeric mutant SOX9-DNA complex increased linearly with increasing SOX9 concentra...
متن کاملA Master Regulator of the Pancreatic Program
Over the last decade, it has been discovered that the transcription factor Sox9 plays several critical roles in governing the development of the embryonic pancreas and the homeostasis of the mature organ. While analysis of pancreata from patients affected by the Sox9 haploinsufficiency syndrome campomelic dysplasia initially alluded to a functional role of Sox9 in pancreatic morphogenesis, tran...
متن کاملThe SOX9 upstream region prone to chromosomal aberrations causing campomelic dysplasia contains multiple cartilage enhancers
Two decades after the discovery that heterozygous mutations within and around SOX9 cause campomelic dysplasia, a generalized skeleton malformation syndrome, it is well established that SOX9 is a master transcription factor in chondrocytes. In contrast, the mechanisms whereby translocations in the --350/-50-kb region 5' of SOX9 cause severe disease and whereby SOX9 expression is specified in cho...
متن کاملA Korean Girl with Campomelic Dysplasia caused by a Novel Nonsense Mutation within the SOX9 Gene
period, and respiratory distress due to laryngotracheomalacia contributes to neonatal death in these patients. Therefore, only a few patients with CMD survive past infancy. Survivors beyond infancy may also have scoliosis, short stature, and hearing loss with age. CMD is caused by haploinsufficiency of the SOX9 gene at 17q24. The SOX9 protein is widely expressed as a transcription factor in man...
متن کاملDominance of SOX9 function over RUNX2 during skeletogenesis.
Mesenchymal stem cell-derived osteochondroprogenitors express two master transcription factors, SOX9 and RUNX2, during condensation of the skeletal anlagen. They are essential for chondrogenesis and osteogenesis, respectively, and their haploinsufficiency causes human skeletal dysplasias. We show that SOX9 directly interacts with RUNX2 and represses its activity via their evolutionarily conserv...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Human molecular genetics
دوره 12 12 شماره
صفحات -
تاریخ انتشار 2003