Heterozygous SOX9 Mutations Allowing for Residual DNA-binding and Transcriptional Activation Lead to the Acampomelic Variant of Campomelic Dysplasia

Abstract

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.

Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9

“…2004; Staffler et al. 2010). Patients with SOX9 mutations manifest campomelia, hypoplastic scapulae, pelvic anomalies, micrognathia, and cleft palate, collectively referred to as campomelic dysplasia (CD), although a certain percentage of mutation‐positive patients show a mild variant of CD that lacks campomelia (acampomelic CD: ACD) (Bernard et al.…”

“…2004; Staffler et al. 2010). SOX9 mutations also result in complete or partial gonadal dysgenesis in individuals with 46,XY karyotype (Meyer et al.…”

Mild Campomelic Dysplasia: Report on a Case and Review

“…Few long-term survivors with CD have been reported [Houston et al, 1983;Gillerot et al, 1989;Meyer et al, 1997;Pfeifer et al, 1999;Giordano et al, 2001;Moog et al, 2001;Mansour et al, 2002;Offiah et al, 2002;Savarirayan et al, 2003;Sock et al, 2003;Hill-Harfe et al, 2005;Velagaleti et al, 2005;Lekovic et al, 2006;Leipoldt et al, 2007;Wada et al, 2009;Staffler et al, 2010]. In general, they share common facial features such as relative macrocephaly, depressed nasal bridge, hypertelorism, high or cleft palate, long philtrum, low-set ears, and micrognathia Offiah et al, 2002;Wada et al, 2009] ( table 1 ).…”

“…The dysplastic nails seen in our patient have been previously reported in 2 CD patients [Moog et al, 2001;Mansour et al, 2002]. It has been postulated that surviving cases: (1) are usually secondary to somatic mosaicism of the SOX9 mutation, (2) depend on the type of the mutation abolishing the expression of the gene or leaving some residual activity of the mutant SOX9 protein, and (3) depend on the presence or absence of a chromosomal rearrangement spearing the coding SOX9 region but affecting the cisregulatory elements upstream of the gene [Meyer et al, 1997;Pfeifer et al, 1999;Giordano et al, 2001;Mansour et al, 2002;Smyk et al, 2007;Staffler et al, 2010]. For instance, the long-term survivors of CD are significantly overrepresented in the group of translocation and inversion cases as compared to the group of CD cases with mutations in the SOX9 coding region [Pfeifer et al, 1999].…”

“…On X-rays, hypoplastic scapulae, defective ischiopubic ossification, hypoplastic patellae, and spinal dysraphism can be seen. Recurrent apnea, upper respiratory infections, kyphoscoliosis, mild learning disabilities, conductive hearing loss, myopia, dislocation of the radial heads and of the hips, and short stature can complicate the course of the disease [Giordano et al, 2001;Moog et al, 2001;Mansour et al, 2002;Leipoldt et al, 2007;Staffler et al, 2010] ( table 1 ). Our patient presented mainly a flat face, relative macrocephaly, long philtrum, micrognathia, limitation of supination and pronation of the forearms, slight developmental delay, and some hear- (2) the mutation p.P170L (c.509C 1 T) detected at heterozygous state in this study.…”