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.
Human SOX9 mutations can lead to either the complete Campomelic Dysplasia syndrome, or isolated clinical features, depending upon whether the mutation occurs in the coding region or in enhancer regions.
Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder.
Heterozygous point mutations and genomic copy-number variant (CNV) deletions involving SOX9 have been reported in patients with campomelic dysplasia (CD), a skeletal malformation syndrome often associated with male-to-female sex reversal.
Since heterozygous mutations within and around SOX9 were shown to cause the severe skeletal malformation syndrome called campomelic dysplasia, researchers around the world have worked assiduously to decipher the many facets of SOX9 actions and regulation in chondrogenesis.
Findings support the notion that more mildly affected, surviving CD/ACD patients carry mutant <i>SOX9</i> alleles with residual expression of SOX9 wild-type protein.
Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and disrupting its distant cis-regulatory elements, have been described in patients with milder forms of campomelic dysplasia, Pierre Robin sequence, and sex reversal.
Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported.
Human mutations in SOX9 or the SOX9 promoter result in campomelic dysplasia, a severe genetic disorder, which disrupts skeletal, craniofacial, cardiac, neural and reproductive development.
Heterozygous loss-of-function coding-sequence mutations of the transcription factor SOX9 cause campomelic dysplasia, a rare skeletal dysplasia with congenital bowing of long bones (campomelia), hypoplastic scapulae, a missing pair of ribs, pelvic, and vertebral malformations, clubbed feet, Pierre Robin sequence (PRS), facial dysmorphia, and disorders of sex development.
We have performed chromosome conformation capture-on-chip (4C) analysis in Sertoli cells and lymphoblasts to verify the proposed long-range interactions of the SOX9 promoter and to identify potential novel regulatory elements that might be responsible for sex reversal in patients with CD.
Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16 Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient.