A novel nonsense mutation, E150X, in the SOX9 gene underlying campomelic dysplasia

Abstract

Campomelic dysplasia (CD) is an autosomal dominant skeletal malformation syndrome with features including bowed lower limbs with pretibial skin dimpling, hypoplastic scapulae and pelvic bones, and 11 pairs of ribs. Mutations in the SOX9 gene have been identified to cause CD. The gene encodes a transcription factor containing a dimerization, a high mobility group, and a C-terminal transactivation (TA) domain. Up to now, 35 SOX9 mutations have been published. In the present study, we describe a Thai girl with clinically and radiologically typical CD. Direct sequencing analysis of the PCR products for the entire coding region of SOX9 revealed that she was heterozygous for a novel 448G > T in exon 2 of SOX9. The DNA change was expected to result in E150X and loss of the entire TA domain. This result further supports that SOX9 is the only gene, discovered to date, responsible for CD across different populations and that the TA domain is important to the function of the normal SOX9.

Clinical and molecular characterization of a Brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations

“…Since changes in SOX9 associated with CD are mainly private mutations, the alterations identified here expand the spectrum of SOX9 pathogenic variations to about seventy ( Table S3 ) ( Thong et al , 2000 ; Giordano et al , 2001 ; Preiss et al , 2001 ; Sock et al , 2003 ; Michel-Calemard et al , 2004 ; Hsiao et al , 2006 ; Shotelersuk et al , 2006 ; Beaulieu et al , 2009 ; Gentilin et al , 2010 ; Okamoto et al , 2010 ; Staffler et al , 2010 ; Kim et al , 2011 ; Stoeva et al , 2011 ; Chen et al , 2012 ; Gopakumar et al , 2013 ; Matsushita et al , 2013 ; Tonni et al , 2013 ). Premature termination codons (PTCs) are the most prevalent mutational class in CD, accounting for approximately 45% of all the alterations identified.…”

A novel SOX9 mutation, 972delC, causes 46,XY sex-reversed campomelic dysplasia with nephrocalcinosis, urolithiasis, and dysgerminoma

“…SOX9 is a member of the SOX (SRY-type high mobility group box) transcription factor family, expressed throughout chondrogenesis and in the genital ridges of both sexes [5]. Approximately 75% of patients with CD have a SOX9 mutation detectible by sequencing [2,6].…”

“…Although 5′ and 3′ genomic alterations have been reported, loss of function coding region SOX9 mutations (approximately 36 to date) occur across the entire reading frame and are typically heterozygous. Campomelic dysplasia is considered dominant because of haploinsufficiency [5].…”

“…Review of SOX9 mutations with or without sex-reversal has yet to yield a genotype-phenotype correlation (Fig. 3) [2][3][4][5][6][7][8][9][10][11][12][13], including unrelated 46,XY cases with identical SOX9 mutations but opposite genital phenotypes and cases demonstrating sex-reversal while lacking an identifiable SOX9 mutation [6]. Our patient's novel SOX9 mutation is informative in this regard but does not clarify this enigma.…”

“…Mutations in cases of sex-reversal are listed below the diagram and in cases without sex-reversal are listed above the diagram. The novel sex-reversing mutation deleting nt972 is in italics [2][3][4][5][6][7][8][9][10][11][12][13].…”