CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

• Published in: European journal of human genetics : EJHG Vol. 17; no. 12; pp. 1560 - 1569
• Main Authors: VAN DIJK, Fleur S, NESBITT, Isabel M, TAN-SINDHUNATA, Gita Mb, VAN RIJN, Rick R, MEIJERS-HEIJBOER, Hanne, COBBEN, Jan M, PALS, Gerard, NIKKELS, Peter Gj, DALTON, Ann, BONGERS, Ernie Mhf, VAN DE KAMP, Jiddeke M, HILHORST-HOFSTEE, Yvonne, DEN HOLLANDER, Nicolette S, LACHMEIJER, Augusta Ma, MARCELIS, Carlo L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2009
• Subjects: Biological and medical sciences; Cartilage; Cell cycle; Child, Preschool; Collagen; Collagen (type I); Diseases of the osteoarticular system; DNA Mutational Analysis; Enzymes; Extracellular Matrix Proteins - genetics; Family; Fatal Outcome; Female; Fetus - abnormalities; Fetus - diagnostic imaging; Fetus - pathology; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic analysis; Genetic screening; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Hydroxylase; Infant, Newborn; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Biology - methods; Mutation; Mutation - genetics; Osteogenesis; Osteogenesis imperfecta; Osteogenesis Imperfecta - diagnostic imaging; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - pathology; Pedigree; Pregnancy; Prenatal diagnosis; Protein deficiency; Proteins; Radiography; Netherlands; CRTAP; Collagen; Diseases of the osteoarticular system; Osteogenesis imperfecta; Recessive character; Genetics; collagen type 1; Mutation; Severe; Osteochondrodysplasia; Genetic disease; recessive
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2009.75

Autosomal recessive lethal and severe osteogenesis imperfecta (OI) is caused by the deficiency of cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase 1 (P3H1) because of CRTAP and LEPRE1 mutations. We analyzed five families in which 10 individuals had a clinical diagnosis of lethal and severe OI with an overmodification of collagen type I on biochemical testing and without a mutation in the collagen type I genes. CRTAP mutations not described earlier were identified in the affected individuals. Although it seems that one important feature of autosomal recessive OI due to CRTAP mutations is the higher consistency of radiological features with OI type II-B/III, differentiation between autosomal dominant and autosomal recessive OI on the basis of clinical, radiological and biochemical investigations proves difficult in the affected individuals reported here. These observations confirm that once a clinical diagnosis of OI has been made in an affected individual, biochemical testing for overmodification of collagen type I should always be combined with molecular genetic analysis of the collagen type I genes. If no mutations in the collagen type I genes are found, additional molecular genetic analysis of the CRTAP and LEPRE1 genes should follow. This approach will allow proper identification of the genetic cause of lethal or severe OI, which is important in providing prenatal diagnosis, preimplantation genetic diagnosis and estimating recurrence risk.