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

Abstract

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

Diverse Regulation but Conserved Function: SOX9 in Vertebrate Sex Determination

“…In addition to these phenotypes in the developing bones and gonads, patients with CMPD may also show defects within other tissues in which SOX9 is expressed, such as brain (e.g., the absence of olfactory bulbs), heart, kidney and lung abnormalities [ 132 ]. Loss-of-function mutations within the coding sequence of SOX9 occur, for example, in the DNA-binding domain HMG-box, the nuclear localisation signals (NLS), or in the transactivating domain ( Figure 6 ) [ 82 , 101 , 128 , 131 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 ]. In some CMPD patients with associated sex reversal, the SOX9 coding sequence is not affected, but translocation breakpoints have been identified in the SOX9 regulatory region up to several hundred kb upstream of SOX9 .…”

A Track Record on SHOX: From Basic Research to Complex Models and Therapy

“…In prehypertrophic chondrocytes, instead, Sox9 is responsible for the activation of Col10a1 , thereby initiating the onset of hypertrophy ( 82 ). Mutations of SOX9 have been associated with campomelic dysplasia, a severe skeletal dysplasia characterized by congenital bowing and angulation of long bones and other skeletal and extraskeletal defects ( 115 ).…”

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

“…The range of functions that Sox proteins serve is broad, including maintaining stem cell features, restricting lineage, and directing terminal differentiation. Germline SOX9 heterozygous inactivating missense and nonsense mutations result in campomelic dysplasia, a syndrome resulting in skeletal malformations, central nervous system dysfunction, as well as abnormalities in other organs [1–2]. …”