Novel exostosin-2 mutation identified in a Chinese family with hereditary multiple osteochondroma

Abstract

Hereditary multiple osteochondroma (HMO) is an autosomal dominant genetic disorder characterized by multiple outgrowing bony tumors capped by cartilage, generally affecting the metaphyses. The disease is known as hereditary multiple exostoses, familial exostosis, multiple cartilaginous exostoses or hereditary malformation of cartilage. The prevalence of HMO in Europe and the Unites States is ~1:100,000, although it has not been reported in China. The disease is often accompanied by pain, asymmetry and skeletal malformations, including forearm and leg bending deformities, limb length discrepancies, and knee internal and external rotation abnormalities. Mutations to exostosin-1 (EXT1) and EXT2 mutations cause insufficient heparan sulfate biosynthesis, leading to chondrocyte proliferation, abnormal bone growth in neighboring regions, multiple exostoses, and ultimately malignant transformation. The risk of malignant degeneration to osteochondrosarcoma increases with age, despite the low lifetime risk (~1%). The present study selected a clinical feature of typical HMO pedigrees, and examined mutations in family members by Sanger sequencing. Each of the five patients examined had a novel heterozygous nonsense mutation, c.67C>T p.Arg23*. The mutation is located prior to the EXT2 exostosin domains in the amino acid sequence and results in a protein truncation of the 705 C-terminal amino acids. The present study provides molecular genetic evidence for a novel causal mechanism of HMO, and provides the basis for clinical genetic counseling for similar diseases.

Keywords: exostosin-2; hereditary multiple osteochondroma; nonsense mutation.

Figure 1.

Pedigree of the Chinese family with hereditary multiple exostoses. The filled symbols represent affected individuals, and empty symbols indicate unaffected family members. The proband (III1; first member of the third generation of the family) is noted with an arrow. There is no consanguinity in this family. Squares indicate male patients, circles indicate female patients. HMO, hereditary multiple osteochondroma.

Figure 2.

Radiograph images of patients, III1 (A and B) and II2 (C and D). (A-D) Multiple osteochondromas are observed around the bilateral knee.

Figure 3.

DNA sequencing was used to identify a novel mutation in the EXT2 gene. (A) The heterozygous nonsense mutation c.67C>T (p.Arg23*) was detected in the EXT2 gene of HMO patients (under panel) but not in that of healthy controls (upper panel). (B) The mutation c.(67C>T), located in exon 2, was predicted to introduce a premature stop codon at position 67, resulting in a truncation of 23 amino acids at the C-terminus of the EXT2 protein. EXT2, exostosin-2; HMO, hereditary multiple osteochondroma.

Figure 4.

Sequence alignment of EXT2 orthologs. EXT2, exostosin-2.

Figure 5.

MutationTaster predicted that the substitution of R23 to the termination codon causes diseases. EXT2, exostosin-2; NMD, nonsense-mediated mRNA decay.