title: Grebe-type chondrodysplasia: a novel missense mutation in a conserved cysteine of the growth differentiation factor 5.
abstract: Grebe-type chondrodysplasia is a congenital skeletal disorder that is characterized by markedly shortened limbs and very short digits. This defect has an autosomal recessive mode of inheritance and results from mutations in the growth differentiation factor 5 (GDF5) gene. Here, we report three affected children in a consanguineous family who display typical features of Grebe-type chondrodysplasia. Sequencing of the GDF5 genes of the affected children identified a novel c.1285T>C mutation encoding a p.Cys429Arg substitution. The Cys429 of human GDF5 belongs to a group of seven cysteines, which are highly conserved across species and among the various members of the transforming factor-beta (TGF-beta) super family of proteins. These cysteines are essential for the structure, processing, and activity of these proteins. Therefore, it is possible that the p.Cys429Arg change in the GDF5 has produced an inactive protein, resulting in a Grebe-type chondrodysplasia phenotype in the affected children. The absence of skeletal abnormalities in the carrier parents suggests that the p.Cys429Arg change did not produce a dominant negative effect or haploinsufficiency in these individuals. This finding differs from the previous report of skeletal abnormalities in heterozygous individuals of Grebe-type chondrodysplasia families.
authors.affiliation: Molecular Genetics Laboratory, Department of Pathology & Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, MBC #10, Riyadh, 11211, Riyadh, Saudi Arabia. MFHaque@Kfshrc.edu.sa
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: Eissa A
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Zaidan
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Shammary
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D055428:Growth Differentiation Factor 5 / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009139:Musculoskeletal Abnormalities; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: D055428:Growth Differentiation Factor 5; D003545:Cysteine