Pseudohypoparathyroidism Type Ib Associated with Novel Duplications in the GNAS Locus

Abstract

Context:

Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype.

Objective:

The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib.

Design:

We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib.

Results:

We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising ~320 kb, occurred ‘de novo’ in the patient, whereas the other one, of ~179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed.

Conclusion:

In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring ‘de novo’ and the other one being maternally inherited.