Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II.

Abstract

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.

• Authors: J Hoogendam, H Farih-Sips, L C Wÿnaendts, C W G M Löwik, J M Wit, M Karperien
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 92 Issue 3 Pg. 1088-95 (Mar 2007) ISSN: 0021-972X [Print] United States
• PMID: 17164305 (Publication Type: Case Reports, Journal Article)

Chemical References

• PTH protein, human
• Parathyroid Hormone
• Receptor, Parathyroid Hormone, Type 1

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• COS Cells
• Cells, Cultured
• Chlorocebus aethiops
• Diagnosis
• Humans
• Infant, Newborn
• Models, Biological
• Molecular Sequence Data
• Mutation
• Osteochondrodysplasias (diagnosis, genetics)
• Parathyroid Hormone (genetics)
• Receptor, Parathyroid Hormone, Type 1 (genetics)
• Transfection