title: 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.
authors.affiliation: Institute of Human Genetics, University of Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Meyer
authors.forename: P
authors.initials: P
authors.lastname: Südbeck
authors.forename: M
authors.initials: M
authors.lastname: Held
authors.forename: T
authors.initials: T
authors.lastname: Wagner
authors.forename: M L
authors.initials: ML
authors.lastname: Schmitz
authors.forename: F D
authors.initials: FD
authors.lastname: Bricarelli
authors.forename: E
authors.initials: E
authors.lastname: Eggermont
authors.forename: U
authors.initials: U
authors.lastname: Friedrich
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: A
authors.initials: A
authors.lastname: Kobelt
authors.forename: J G
authors.initials: JG
authors.lastname: Leroy
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: E
authors.initials: E
authors.lastname: Michel
authors.forename: B
authors.initials: B
authors.lastname: Mitulla
authors.forename: R A
authors.initials: RA
authors.lastname: Pfeiffer
authors.forename: A
authors.initials: A
authors.lastname: Schinzel
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Scherer
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D012734:Disorders of Sex Development; D005260:Female; D005796:Genes; D005838:Genotype; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D012008:Recurrence; D055758:SOX9 Transcription Factor; D012732:Sex Determination Analysis; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors