Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum

• Published in: Human genetics Vol. 122; no. 3-4; pp. 389 - 395
• Main Authors: Ali, Bassam R., Jeffery, Steve, Patel, Neha, Tinworth, Lorna E., Meguid, Nagwa, Patton, Michael A., Afzal, Ali R.
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.11.2007; Berlin Springer Nature B.V; New York, NY
• Subjects: Adolescent; Animals; Base Sequence; Biological and medical sciences; Bone Diseases, Developmental - genetics; Bone Diseases, Developmental - metabolism; Cell Membrane - metabolism; Child; Classical genetics, quantitative genetics, hybrids; Cysteine; Diseases of the osteoarticular system; DNA Primers - genetics; Endoplasmic Reticulum - metabolism; Female; Frizzled Receptors - chemistry; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; Fundamental and applied biological sciences. Psychology; Genes, Recessive; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; HeLa Cells; Homozygote; Human; Humans; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mice; Mice, Mutant Strains; Mutation, Missense; Phenotype; Protein Structure, Tertiary; Protein Transport; Proteins; Receptor Tyrosine Kinase-like Orphan Receptors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Syndrome; Transfection; Tyrosine; Proximal; Diseases of the osteoarticular system; Genetics; Robinow syndrome; Mutation; Osteochondrodysplasia; Endoplasmic reticulum
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-007-0409-0

ROR2 is a member of the cell surface receptor tyrosine kinase (RTKs) family of proteins and is involved in the developmental morphogenesis of the skeletal, cardiovascular and genital systems. Mutations in ROR2 have been shown to cause two distinct human disorders, autosomal recessive Robinow syndrome and dominantly inherited Brachydactyly type B. The recessive form of Robinow syndrome is a disorder caused by loss-of-function mutations whereas Brachydactyly type B is a dominant disease and is presumably caused by gain-of-function mutations in the same gene. We have previously established that all the missense mutations causing Robinow syndrome in ROR2 are retained in the endoplasmic reticulum and therefore concluded that their loss of function is due to a defect in their intracellular trafficking. These mutations were in the distal portion of the frizzled-like cysteine rich domain and kringle domain. Here we report the identification of two novel mutations in the frizzled-like cysteine-rich domain of ROR2 causing Robinow syndrome. We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane. The clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2 suggests a stringent requirement for the correct folding of this domain prior to export of ROR2 from the endoplasmic reticulum to the plasma membrane.