Heterozygous SOX9 mutations allowing for residual DNA-binding and transcriptional activation lead to the acampomelic variant of campomelic dysplasia.
Campomelic dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal acampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent.
Staffler
Alex
A
Dr. von Hauner Children's Hospital, Ludwig-Maximilian-University, 80337 Munich, Germany.
Hammel
Markus
M
Wahlbuhl
Mandy
M
Bidlingmaier
Christoph
C
Flemmer
Andreas W
AW
Pagel
Philipp
P
Nicolai
Thomas
T
Wegner
Michael
M
Holzinger
Andreas
A
D000818:Animals; D019556:COS Cells; D055036:Campomelic Dysplasia / Q000235:genetics* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D011485:Protein Binding; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D004247:DNA