A novel COMP mutation in a pseudoachondroplasia family of Chinese origin

We investigated a four-generation PSACH pedigree of Chinese Han origin. Two patients and two unaffected individuals were recruited for clinical evaluation and molecular genetic analysis. The genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was adopted to amplify the 8-19 exons of COMP gene. Then the products were sequenced bi-directionally for screening mutation. Clinical evaluation revealed that PSACH patients in this pedigree had a severe disproportionate short stature (-10SD). A heterozygous TGTCCCTGG insertion in exon 13, between nucleotide 1352T and 1353G, were identified in the patients except the unaffected individuals, which resulted in a three-amino-acid insertion (451V_452P ins VPG) in the sixth calmodulin-like repeat of the COMP protein.This c. 1352_1353ins TGTCCCTGG is a novel mutation responsible for severe familial PSACH.Pseudoachondroplasia (PSACH, OMIM 177170) is a rare autosomal dominant osteochondrodysplasia characterized by typical disproportionate short stature, brachydactyly, lower limbs anomalies, joint laxity, scoliosis, early onset osteoarthritis, epiphyseal and metaphyseal abnormalities. It is estimated to affect at least 1 in 20,000 persons [1,2]. The affected individual has a normal length at birth,and growth retardation generally will not be recognized until two or three years of age. Notably, all patients have normal craniofacial appearance and intelligence [1,3-5].The PSACH gene was initially localized to chromosome 19 in 1993 [6,7]. Mutations on the Cartilage Oligomeric Matrix Protein (COMP) gene were subsequently found to cause PSACH and another skeletal dysplasia, multiple epiphyseal dysplasia [8,9]. COMP protein is a large secreted pentameric glycoprotein of the thrombospondin family, expressed in the extracellular matrix (ECM) surrounding the cells that make up ligaments and tendons. COMP monomer consists of an amino-terminal domain, four type IIepidermal growth like repeats, eight type II