COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia

Abstract

The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.

Identification of novel and recurrent mutations in the calcium binding type III repeats of cartilage oligomeric matrix protein in patients with pseudoachondroplasia

“…Within this region, six causative mutations have been identified, D399N, D401N, C407F, D408Y, C410Y, and N415K (Loughlin et al, 1998;Kennedy et al, 2005a;Zankl et al, 2007). Interestingly, D397Y and C407Y are associated with PSACH, but the other six mutations all caused MED, especially C407, when substituted for different amino acids, leading to diverse phenotypes.…”

Mutations Targeting Intermodular Interfaces or Calcium Binding Destabilize the Thrombospondin-2 Signature Domain

“…Only two of the 37 sites that are different between mouse (Ser 882 and Thr 955 ) and human THBS-2 (Ala 882 and Ser 955 ) signature domain proteins are sites of disease-causing mutations in THBS-5 (S454R and T527A) (32,33), and at these two sites the mouse THBS-2 signature domain has the same amino acids as the wild-type human THBS-5 signature domain. We have mapped the 37 differences between mouse and human THBS-2 signature domain proteins on the crystal structure of the human THBS-2 protein and found only one pair of residues (Ser 955 -Ile 941 ) that are within 4 Å of one another, as is regularly the case when the protein in one species contains a residue that causes disease when present in the homologous protein of another species and is accompanied by an apparently compensating change of a nearby residue (34).…”

Unique Matrix Structure in the Rough Endoplasmic Reticulum Cisternae of Pseudoachondroplasia Chondrocytes

“…14 -17 Many novel mutations have been identified as causing these disorders, with the majority of mutations found in the highly conserved type 3 calciumbinding repeat domain. 17,18 In comparison, only a few mutations have been identified outside of this region and only in the C-terminal globular domain. 19 The type 3 repeats are highly conserved in all thrombospondins, suggesting that this region is critical for protein function.…”