Genetic study of SOX9 in a case of campomelic dysplasia

Campomelic dysplasia (CD) is a sporadic autosomal dominant syndrome that re sults in skeletal malformation and developmental abnormalities. Death usual ly occurs neonatally as a result of respiratory insufficiencies, but life e xpectancy varies depending on the severity of the phenotype, XY sex reversa l is common in CD, and a range of genital defects is observed in males and females, CD is due to mutations in SOX9, a member of the SOX (SRY-related H MG box) gene family. SOX9 is a transcription factor involved in chondrogene sis and sex determination. We present a CD patient with a normal 46,XX kary otype and female phenotype, Single-stranded conformation polymorphism analy sis of DNA from this CD patient demonstrated a single-stranded conformation polymorphism shift in the C-terminal region of SOX9, DNA sequencing showed a frameshift mutation resulting from the insertion of a single guanine res idue in nucleotide region 1,453-1,456. This insertion mutation creates a mu tant SOX9 open reading frame that is 201 nucleotides longer than the normal gene. It has been shown that the C-terminal region of SOX9 is responsible for the transactivating ability of the protein. The frameshift identified h ere affects approximately half of the protein region needed for full transa ctivating function, We hypothesize that residual SOX9 function may explain why this patient survived infancy. (C) 2001 Wiley-Liss, Inc.