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Novel Mutations in the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Type 1 Causing Blomstrand Osteochondrodysplasia Types I and II

Departments of Pediatrics (J.H., J.M.W., M.K.) and Endocrinology and Metabolic Diseases (H.F.-S., C.W.G.M.L., M.K.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Pathology (L.C.W.), Free University Amsterdam, 1007 MB Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: M. Karperien, Leiden University Medical Center, Department of Endocrinology, C4R89, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: karperien{at}lumc.nl.

Context: 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.

Design and Patients: 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.