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A mutation creating an upstream initiation codon in the SOX9 5' UTR causes acampomelic campomelic dysplasia.
von Bohlen, Anna E; Böhm, Johann; Pop, Ramona; Johnson, Diana S; Tolmie, John; Stücker, Ralf; Morris-Rosendahl, Deborah; Scherer, Gerd.
Affiliation
  • von Bohlen AE; Institute of Human GeneticsUniversity of FreiburgFreiburgGermany.
  • Böhm J; Present address: Klinik für AnästhesiologieOperative Intensivmedizin und SchmerztherapieUniklinikum Gießen und MarburgGießenGermany.
  • Pop R; Institute of Human GeneticsUniversity of FreiburgFreiburgGermany.
  • Johnson DS; Present address: Department of Translational Medicine and NeurogeneticsIGBMCIllkirchFrance.
  • Tolmie J; Institute of Human GeneticsUniversity of FreiburgFreiburgGermany.
  • Stücker R; Present address: Broad Institute of MIT and HarvardCambridgeMassachusetts02142USA.
  • Morris-Rosendahl D; Present address: Harvard Stem Cell InstituteCambridgeMassachusetts02138USA.
  • Scherer G; Present address: Department of Stem Cell and Regenerative BiologyHarvard UniversityCambridgeMassachusetts02138USA.
Mol Genet Genomic Med ; 5(3): 261-268, 2017 May.
Article in En | MEDLINE | ID: mdl-28546996
ABSTRACT

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.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Etiology_studies Language: En Journal: Mol Genet Genomic Med Year: 2017 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Etiology_studies Language: En Journal: Mol Genet Genomic Med Year: 2017 Type: Article