Context: The Parathyroid Hormone (PTH)/PTH-related peptide (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 2 families with type I and in 3 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 (intronM4+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 2 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.