Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-05-29
2000-11-07
Priebe, Scott D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 235, 4353201, 435 691, 435325, 514 44, 424 9321, C07H 2104
Patent
active
061438782
DESCRIPTION:
BRIEF SUMMARY
THIS INVENTION relates to the Sox-9(SOX-9 in humans) gene which appears to have a role in mammalian skeletal development and which is also related to the inherited skeletal disease syndrome Campomalic Dysplasia (CD), alternatively known as campomelic dwarfism or campomelic syndrome.
FIELD OF THE INVENTION
CD is an osteochondrodysplasia affecting 0.05-2.2 per 10,000 live births. It is characterised by congenital bowing and angulation of the long bones, together with other skeletal defects, The scapulae are very small and the pelvis and the spine show changes. One pair of ribs is usually missing. Severe anomalies of the lower cervical spine are seen. The interior part of the scapula is hypoplastic. Cleft palate, micrognethia, flat face and hypertension are also features. Various defects of the ear have been noted, affecting the cochlea, malleus, incus, stapes and tympanum. Most patients die in the neonatal period of respiratory distress which has been attributed to hypoplsia of tracheobronchial cartilage (Lee et al., 1972, Am. J. Dis. Child, 124, 485-496) and small thoracic cage (Houston et al., 1983, Am. J. Med. Genet., 15, 3-28).
The human SOX-9 gene has been mapped to chromosome 17 within a region which also contains CMPD1, the locus for CD.
Chromosomal localisation of CMPD1 was based on three independent, apparently balanced, de novo reciprocal translocation involving chromosome 17 (Tommerup et al., 1993, Nature Genet., 4, 170-174). All three translocations had breakpoints between 17q24 and q25, distal to the growth hormone locus (GH) but proximal to thymidine kinase (TK-1). This mapping excluded previous CMPD1 candidates HOX2 and COL1A1. Mutations within the SOX-9 gene have now been found in DNA from CD patients (Foster et al., Nature, in press; Wagner et al., Cell, in press) proving that the SOX-9 gene has a role in skeletal development. Curiously, CD is often associated with sex reversal (Hovmoller et al., 1977, Hereditas, 86, 51-62). Among 33 cases with CD and an XY karyotype, 21 were phenotypic females and two were intersexes (Houston et al., 1983, supra). This association defines an autosomal sex-reversal locus SRA1 at or near the CMPD1 locus.
Recurrent observations of CD in sibs and occasional consanguinity in CD-affected families have led to the belief that CD is inherited as an autosomal recessive disorder. However, a total of five independent de novo chromosomal rearrangements associated with CD lends some support to a dominant, usually lethal mutation (Tommerup et al., 1993, supra). This may explain a case of CD affecting a mother and daughter, although it is possible that the milder phenotype in these patients represents a different mutation (Lynch et al., 1993, J. Med. Genet., 30, 683-686).
The murine Sox-9 gene has been mapped to distal mouse chromosome 11. This region contains various disease loci including Ts, the locus for the mouse mutant Tail-short.
Tommerup et al., 1993, above, have noted the similarities between CD and Tail-short (Ts), which also maps between Gh and Tk-1 of mouse chromosome 11 (Buchberg et al., 1992, Mammal, Genome, 3, 5162-181). No sex reversal has been associated with Ts. It is not yet clear whether the same gene is affected in both CD and Tail-short. The similarity between the two phenotypes raises the intriguing possibility that the human mutation would be homozygous lethal at the blastocyst stage, with heterozygosity resulting in the campomelic phenotype.
Ts is a mouse developmental mutant first described by Morgan, 1950, J. Hered., 41, 208-215. The mutation is semi-dominant: homozygotes die at the blastocyst stage, before or shortly after implantation (Paterson, 1980, J. Expt. Zool., 211, 247-256). Heterozygotes are small with kinked tails and numerous other skeletal defects. The phenotype is variable, but typical abnormalities have been described (Deol, 1961, Proc. R. Soc. Lon. B., 155, 78-95). The short, kinked tall is caused by reduced number and dysmorphology of caudal vertebrae. Vertebral fusions and dyssymphyses also affect the presacral and sacral reg
REFERENCES:
Chardard et al. (Nucleic Acids Research 21, 15, p. 357), 1993.
Wagner et al. (Cell, vol. 79, pp. 1111-1120), Dec. 1994.
Mundlos et al. (FASEB J., 11, 2, 1997, 125-132), 1997.
Verma et al., Nature, vol. 389, pp. 239-242, 1997.
Gunzburg et al. (Molecular Medicine Today, pp. 410-417, 1995.
Ngo et al., in: The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al., (ed.), Birkhauser, Boston, MA, pp. 433 and 492-494, 1994.
P. Denney et al. (1992) "A conserved family of genes related to the testis determining gene, SRY" Nucleic Acid Research 20(11): 2887.
E.M. Wright (1993) "Seven new members of the Sox gene family expressed during mouse development" Nucleic Acid Research 21(3): 744.
C. Goze et al. (1993) "Partial Cloning of SOX-11 and SOX-12, two new human SOX genes" Nucleic Acid Research 21(12): 2943.
J.W. Foster et al. (1994) "Camponelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene" Nature 372: 525-530.
E. Wright et al. (1995) "The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos" Nature Genetics9: 15-20.
J.R. Hawkins (1995) "Commentary: Genetics of XY sex reversal" Journal of Endocrinology 147: 183-187.
Goodfellow Peter Neville
Koopman Peter Anthony
Nguyen Dave Trong
Priebe Scott D.
The University of Queensland
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