Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

Abstract

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

“…The SOX9 nonsense mutation p.Y440* is recurrently seen in patients with acampomelic campomelic dysplasia (MIM114290) [34][35][36] , a severe form of skeletal dysplasia. Variable survival time of patients with this same mutation and lack of clear genotype-phenotype correlation among patients suggest that genetic modifiers that affect phenotypic variability may exist.…”

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

“…Known SOX9 mutations include various missense substitutions in the high‐mobility group or dimerization domains, as well as several nonsense, frameshift, and splice‐site mutations widely distributed in the coding region (Meyer et al. 1997; Bernard et al. 2003; Harley et al.…”

“…SOX9 mutations also result in complete or partial gonadal dysgenesis in individuals with 46,XY karyotype (Meyer et al. 1997; Michel‐Calemard et al. 2004).…”

LSox5 regulates RhoB expression in the neural tube and promotes generation of the neural crest

“…Indeed, it is in this process that LSox5 has been most thoroughly studied. Mutations in SOX9 produce campomelic dysplasia, a syndrome that is often associated with autosomal XY sex reversal and involves the severe malformation of most cartilage-derived structures (Meyer et al, 1997). Furthermore, mouse chimeras containing Sox9 -/-embryonic stem cells inactivate early cartilage markers, including the Col2a1 gene (Bi et al, 1999), a phenomenon that is also observed in Sox5, Sox6 double mutant embryos (Smits et al, 2001).…”