title: CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis.
abstract: 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.
authors: Department of Clinical Genetics, VU University Medical Cen, Amsterdam, The Netherlands. fs.vandijk2@vumc.nl
authors: Fleur S
authors: FS
authors: Van Dijk
authors: Isabel M
authors: IM
authors: Nesbitt
authors: Peter G J
authors: PG
authors: Nikkels
authors: Ann
authors: A
authors: Dalton
authors: Ernie M H F
authors: EM
authors: Bongers
authors: Jiddeke M
authors: JM
authors: van de Kamp
authors: Yvonne
authors: Y
authors: Hilhorst-Hofstee
authors: Nicolette S
authors: NS
authors: Den Hollander
authors: Augusta M A
authors: AM
authors: Lachmeijer
authors: Carlo L
authors: CL
authors: Marcelis
authors: Gita M B
authors: GM
authors: Tan-Sindhunata
authors: Rick R
authors: RR
authors: van Rijn
authors: Hanne
authors: H
authors: Meijers-Heijboer
authors: Jan M
authors: JM
authors: Cobben
authors: Gerard
authors: G
authors: Pals
mesh_terms: D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005190:Family; D017809:Fatal Outcome; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008967:Molecular Biology / Q000379:methods*; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011247:Pregnancy; D011859:Radiography
chemical_list: C108053:CRTAP protein, human; D016326:Extracellular Matrix Proteins; D018832:Molecular Chaperones