Abstract
BackgroundCampomelic dysplasia (CD) is a semilethal developmental disorder caused by mutations in and around SOX9. CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the acampomelic form of CD (ACD).MethodsThis is a single case report on a patient with clinical and radiological features of ACD who has no mutation in the SOX9 protein‐coding sequence nor a translocation with breakpoint in the SOX9 regulatory domain. We include functional studies of the novel mutant protein in vitro and in cultured cells.ResultsThe patient was found to have a de novo heterozygous mutation c.‐185G>A in the SOX9 5′UTR. The mutation creates an upstream translation start codon, uAUG, with a much better fit of its flanking sequence to the Kozak consensus than the wild‐type AUG. By in vitro transcription‐translation and transient transfection into COS‐7 cells, we show that the uAUG leads to translation of a short peptide from a reading frame that terminates just after the wild‐type AUG start codon. This results in reduced translation of the wild‐type protein, compatible with the milder phenotype of the patient.ConclusionFindings support the notion that more mildly affected, surviving CD/ACD patients carry mutant SOX9 alleles with residual expression of SOX9 wild‐type protein. Although rarely described in human genetic disease and for the first time here for CD, mutations creating upstream AUG codons may be more common than generally assumed.
Highlights
By in vitro transcription-translation and transient transfection into COS-7 cells, we show that the upstream AUG (uAUG) leads to translation of a short peptide from a reading frame that terminates just after the wild-type AUG start codon
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Campomelic dysplasia (CD; MIM #114290) is a semilethal skeletal malformation syndrome characterized by macrocephaly, mid-face hypoplasia, Robin sequence, hip dislocation, bowed femora and tibiae, talipes, and respiratory distress
Summary
Campomelic dysplasia (CD; MIM #114290) is a semilethal skeletal malformation syndrome characterized by macrocephaly, mid-face hypoplasia, Robin sequence, hip dislocation, bowed femora and tibiae (i.e., campomelia), talipes, and respiratory distress. Radiological features include hypoplastic scapulae, small chest, 11 rib pairs, undermineralized thoracic pedicles, kyphosis or scoliosis, pelvic malformations, bowing of femora and tibiae, hypoplastic fibulae, and short first metacarpals (Mansour et al 1995; Unger et al 2013). About 10% of cases missing the eponymous feature of campomelia are referred to as acampomelic CD (ACD). CD/ACD individuals who survive the neonatal period may have a number of complications, the most common of which include recurrent apnea/respiratory tract infection, progressive kyphoscoliosis, short stature, dislocation of the hips, conductive hearing loss, and mild to moderate learning difficulties (Mansour et al 2002). Surviving patients frequently have the acampomelic form of CD (ACD)
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