Open AccessA mutation creating an upstream initiation codon in the SOX 9 5′ UTR causes acampomelic campomelic dysplasia
Author(s) -
Bohlen Anna E.,
Böhm Johann,
Pop Ramona,
Johnson Diana S.,
Tolmie John,
Stücker Ralf,
MorrisRosendahl Deborah,
Scherer Gerd
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.282
Subject(s) - start codon , genetics , mutant , stop codon , untranslated region , biology , mutation , five prime untranslated region , mutant protein , open reading frame , microbiology and biotechnology , wild type , phenotype , gene , messenger rna , peptide sequence
Background Campomelic dysplasia ( CD ) is a semilethal developmental disorder caused by mutations in and around SOX 9 . 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 SOX 9 protein‐coding sequence nor a translocation with breakpoint in the SOX 9 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 SOX 9 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 SOX 9 alleles with residual expression of SOX 9 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.