A mutation creating an upstream initiation codon in the SOX9 5′ UTR causes acampomelic campomelic dysplasia

Background Campomelic 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). Methods This i...

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Bibliographic Details
Published in:Molecular genetics & genomic medicine 2017-05, Vol.5 (3), p.261-268
Main Authors: Bohlen, Anna E., Böhm, Johann, Pop, Ramona, Johnson, Diana S., Tolmie, John, Stücker, Ralf, Morris‐Rosendahl, Deborah, Scherer, Gerd
Format: Article
Language:English
Subjects:
Campomelic dysplasia
Kozak consensus
Original
SOX9
uAUG
uORF
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Summary:Background Campomelic 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). Methods This 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. Results The 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. Conclusion Findings 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. We report the first CD/ACD case with a de novo base substitution in the 5' UTR of SOX9 that generates a functional upstream start codon and an upstream ORF that is out‐of‐frame with the main coding sequence, leading to reduced but not completely abolished expression of the normal ORF. Our study corroborates the notion that more mildly affected, surviving CD/ACD patients carry mutant SOX9 alleles with residual expression of SOX9 wild‐type protein.
ISSN:2324-9269
2324-9269
DOI:10.1002/mgg3.282