title: Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II.
abstract: BACKGROUND
  The PTH/PTHrP receptor type 1 (PTHR1) has a key role in endochondral ossification, which is emphasized by diseases resulting from mutations in the PTHR1 gene. Among these diseases is Blomstrand osteochondrodysplasia (BOCD).
  
  
  OBJECTIVE
  BOCD can be divided into two types, depending on the severity of the skeletal abnormalities. The molecular basis for this heterogenic presentation is unknown.
  
  
  METHODS
  We performed mutation analysis in two families with type I and in three families with the less severe form of BOCD type II.
  
  
  RESULTS
  In one of the type I BOCD cases, a homozygous nonsense mutation (R104X) was found, resulting in a truncated PTHR1. In the second type I BOCD case, no mutation was found. A homozygous nucleotide change (intron M4+27C>T) was demonstrated in one of the type II BOCD cases creating a novel splice site. In dermal fibroblasts of the patient, this novel splice site was preferentially used, resulting in an aberrant transcript. The wild-type transcript remained, however, present, albeit at low levels. In the other two families with type II BOCD, a previously identified homozygous missense mutation (P132L) was found. Functional analysis demonstrated that the P132L mutant had low residual activity.
  
  
  CONCLUSIONS
  In combination with data presented in literature, we conclude that type I BOCD is caused by a complete inactivation of the PTHR1, whereas low levels of residual activity due to a near complete inactivation of the PTHR1 result in the relatively milder presentation of type II BOCD.
authors.affiliation: Leiden University Medical Center, Department of Pediatrics, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Hoogendam
authors.forename: H
authors.initials: H
authors.lastname: Farih-Sips
authors.forename: L C
authors.initials: LC
authors.lastname: Wÿnaendts
authors.forename: C W G M
authors.initials: CW
authors.lastname: Löwik
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
authors.forename: M
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003933:Diagnosis; D006801:Humans; D007231:Infant, Newborn; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D010281:Parathyroid Hormone / Q000235:genetics*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D014162:Transfection
chemical_list: C470125:PTH protein, human; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1